Heterocyclic derivatives and their use in the treatment of neurological disorders

ABSTRACT

The invention relates to novel heterocyclic compounds of the formula 
                         
in which all of the variables are as defined in the specification, pharmaceutical compositions thereof, combinations thereof, and their use as medicaments, particularly for the treatment of Alzheimer&#39;s Disease or diabetes via inhibition of BACE-1 or BACE-2.

PRIORITY CLAIM

This application is a divisional of U.S. patent application Ser. No.15/385,147 filed Dec. 20, 2016, which is a divisional of U.S. patentapplication Ser. No. 14/482,662 filed Sep. 10, 2014, issued as U.S. Pat.No. 9,550,758 on Jan. 24, 2017, which is a divisional of U.S. patentapplication Ser. No. 14/136,855 filed Dec. 20, 2013, issued as U.S. Pat.No. 8,865,712 on Oct. 21, 2014, which is a continuation of U.S. patentapplication Ser. No. 13/348,039 filed on Jan. 11, 2012, issued as U.S.Pat. No. 8,637,508 on Jan. 28, 2014, which claims priority to U.S.Provisional Patent Application No. 61/534,591 filed Sep. 14, 2011, andIndian Patent application No. 77/DEL/2011 filed on Jan. 13, 2011. Theentire contents of the aforementioned applications are hereinincorporated by reference.

FIELD OF THE INVENTION

The invention relates to novel heterocyclic derivatives andpharmaceutically acceptable salts thereof, pharmaceutical compositionsthereof, pharmaceutical combinations thereof, and their use asmedicaments, particularly for the treatment of neurodegeneration viainhibition of BACE-1 or diabetes via inhibition of BACE-2.

BACKGROUND OF THE INVENTION

Alzheimer's Disease is a devastating neurodegenerative disorder. Itssporadic forms affect an elderly population (sharp increase in incidenceat >75 years of age), in addition, there are various familial forms withan onset of the disease in the fourth or fifth decade of life.Pathologically, it is characterized by the presence of extracellularsenile plaques, and intracellular neurofibrillar tangles in patient'sbrains. The core constituent of the senile plaques are small, 4 kDaamyloid peptides. They are generated by the proteolytic processing of alarge transmembrane protein, amyloid precursor protein (APP). Cleavageof APP by beta-secretase (BACE-1) releases the soluble APP-betafragment, while the 99-amino acid long C-terminus remains tethered tothe membrane. This C-terminal fragment is subsequently proteolyticallyprocessed by gamma-secretase (a membrane multi-enzyme complex) togenerate amyloid peptides of various length, predominantly 40 and 42amino acids long (Hardy J, Selkoe D J (2002) Science; 297(5580):353-356).

If, under pathologic conditions, the generation of these peptides occursat an increased rate, or if their removal from the brain is disturbed,increased brain amyloid peptide concentrations leads to the formation ofoligomers, fibrils and eventually plaques (Farris W, et al (2007) Am. J.Pathol.; 171 (1):241-251). It has been shown, that deposition of amyloidpeptides and plaques in the brain is the first measurable event in thepathogenesis of Alzheimers Disease, and that it is the trigger for lossof synapses, synaptic contacts, and neurons (Grimmer T, et al (2009)Neurobiology of Aging; 30 (12):1902-1909). Brain atrophy caused bymassive neuron loss is followed by impairments in cognition, memory,orientation and the ability to perform the tasks of daily living, i.e.clinically manifest dementia (Okello A, et al (2009) Neurology; 73(10):754-760).

BACE-1, also known as Asp2 or Memapsin 2, is a transmembrane asparticprotease highly expressed in neurons. It co-localizes with its substrateAPP in Golgi and endocytic compartments (Willem M, Lammich S, Haass C(2009) Semin. Cell Dev. Biol; 20 (2):175-182). Knock-out studies in micehave demonstrated the absence of amyloid peptide formation, while theanimals are healthy and fertile (Ohno M, et al (2007) Neurobiol. Dis.;26 (1):134-145). Genetic ablation of BACE-1 in APP-overexpressing micehas demonstrated absence of plaque formation and the reversal ofcognitive deficits (Ohno M, et al (2004) Neuron; 41 (1):27-33). BACE-1levels are elevated in the brains of sporadic Alzheimer's Diseasepatients (Hampel H, Shen Y (2009) Scand. J. Clin. Lab. Invest.; 69(1):8-12).

Taken together, these findings suggest that the inhibition of BACE-1 maybe a favourable therapeutic strategy for the treatment of Alzheimer'sDisease.

Beta-site amyloid precursor protein cleaving enzyme 2 (BACE-2) is atransmembrane aspartic protease that is highly expressed in pancreatic βcells and other peripheral tissues (Brian D. Bennett, Safura Babu-Khan,Richard Loeloff, Jean-Claude Louis, Eileen Curran; Martin Citron, andRobert Vassar (2000) JJ. Biol. Chem. 275 (27) 20647-20651). BACE-2 isclosely related to BACE-1 or beta secretase. However, despite structuraland sequence similarities the substrate specificity of BACE-1 and BACE-2appear to be different. While Aβ or β-amyloid peptide is the mainsubstrate of BACE-1, BACE-2 does not generate either form of Aβ (Vassar,R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P.,Teplow, D. B., Ross, S., Amarante, P., Loeloff, R., Luo, Y., Fisher, S.,Fuller, J., Edenson, S., Lile, J., Jarosinski, M. A., Biere, A. L.,Curran, E., Burgess, T., Louis, J.-C., Collins, F., Treanor, J., Rogers,G., and Citron, M. (1999) Science 286, 735-741).

Transmembrane protein 27 (TMEM27 or collectrin) plays an important rolein β-cell proliferation and insulin secretion (Pinar Akpinar, SatoruKuwajima, Jan Kriitzfeldt, and Markus Stoffel (2005) Tmem27: CellMetabolism. 2(6) 385-397) and has been identified as a substrate forBACE-2 (WO 2010/063718). Tmem27 exists as a dimer and the extracellulardomain is cleaved and shed from the plasma in a β cell-specific manner.Overexpression of full-length Tmem27, but not the truncated or solubleprotein, increases β cell proliferation, suggesting that the full lengthprotein is required for this biological function. Tcf1 (hepatocytenuclear factor-1α, HNF-1α) controls the transcription of TMEM27. Micewith targeted deletion of Tcf1 exhibit decreased β cell mass, andknockdown of Tmem27 using RNAi results in a reduction of cellproliferation. Transgenic mice with increased expression of Tmem27 inpancreatic β cells exhibit increased β cell mass compared to theirwild-type littermates. This data indicates that TMEM27 μlays a role incontrol of β cell mass and that inhibition of BACE-2 which cleavesTMEM27 could be useful for treating loss of β cell mass and function,the underlying cause of diabetes.

Taken together, these findings suggest that the inhibition of BACE-2 maybe a favourable therapeutic strategy for the treatment and prevention ofmetabolic disorders related to decreased β cell mass and/or function,such as type 2 diabetes.

SUMMARY OF THE INVENTION

The present invention relates to novel heterocyclic derivatives havingBACE inhibitory activity, to their preparation, to their medical use andto medicaments comprising them.

More particularly, in a first aspect, the invention relates to acompound of the formula

in which

-   -   either    -   X₁ is CR₁ or N;    -   X₃ is CR₃ or N;    -   X₄ is CR₄ or N;    -   X₅ is CR₅ or N;    -   wherein at least one of X₁, X₃, X₄ and X₅ is N and not more than        2 of X₁, X₃, X₄ and X₅ are N;    -   or    -   X₁ is CR₁ or N;    -   X₃ is CR₃, N or S;    -   X₄ is a bond;    -   X₅ is CR₅, N or S;    -   wherein at least one of X₁, X₃ and X₅ is N or S, not more than 2        of X₁, X₃ and X₅ are N and not more than 1 of X₃ and X₅ are S;    -   R₁ is hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy,        (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,        (C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,        (C₂₋₈)alkenyl, or (C₂₋₈)alkynyl;    -   R₂ is an aryl, heteroaryl or non-aromatic heterocyclyl group G₁,        which group G₁ is optionally substituted by 1, 2, 3 or 4        substituents independently selected from the group, consisting        of cyano, amino, amino-(C₁₋₈)alkyl,        N—(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl,        N,N-di(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, aminocarbonyl,        thiocarbamoyl, halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl,        hydroxy, oxo, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy,        (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,        (C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₃₋₈)cycloalkyl-(C₁₋₈)alkoxy,        (C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,        (C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,        (C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl, (C₂₋₈)alkynyl,        (C₂₋₈)alkenoxy, (C₂₋₈)alkynoxy and a (C₃₋₈)cycloalkyl, aryl,        heteroaryl or non-aromatic heterocyclyl group G₂, which group G₂        is optionally substituted by 1, 2, 3, or 4 substituents        independently selected from the group, consisting of cyano,        aminocarbonyl, halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl,        hydroxy, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio,        halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,        (C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,        (C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,        (C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl and        (C₂₋₈)alkynyl;    -   R₃ is hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy; halogen-(C₁₋₈)alkoxy,        (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,        (C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,        (C₂₋₈)alkenyl, or (C₂₋₈)alkynyl;    -   R₄ is hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy,        (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,        (C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,        (C₂₋₈)alkenyl, or (C₂₋₈)alkynyl;    -   R₅ is hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy,        (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,        (C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,        (C₂₋₈)alkenyl, or (C₂₋₈)alkynyl;    -   or    -   R₄ and R₅, taken together, are —C(H)═C(H)—C(H)═C(H)— or a        (C₁₋₈)alkylene group, in which (C₁₋₈)alkylene group 1 or 2 —CH₂—        ring members are optionally replaced with hetero ring members        independently selected from the group, consisting of —N(H)—,        —N[(C₁₋₈)alkyl]-, —O—, —S—, —S(═O)— or —S(═O)₂—;    -   R₆ is (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl, hydroxy-(C₁₋₈)alkyl,        (C₁₋₈)alkoxy-(C₁₋₈)alkyl, mercapto-(C₁₋₈)alkyl,        (C₁₋₈)alkylthio-(C₁₋₈)alkyl, amino-(C₁₋₈)alkyl,        N—(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl,        N,N-di(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, (C₂₋₈)alkenyl, or        (C₂₋₈)alkynyl;    -   or    -   R₅ and R₆, taken together, are a (C₁₋₄ alkylene group, in which        (C₁₋₄ alkylene group 1 —CH₂— ring member is optionally replaced        with a hetero ring member independently selected from the group,        consisting of —N(H)—, —O—, —S—, —S(═O)— or —S(═O)₂—;    -   E₁ is —C(R₇)(R₈)—, or —C(R₇)(R₈)—C(R₉)(R₁₀)—;    -   E₂ is —C(R₁₁)(R₁₂)—, or —C(R₁₁)(R₁₂)—C(R₁₃)(R₁₄)—;    -   either    -   each of R₇ and R₈ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;    -   or    -   R₇ and R₈, taken together, are oxo or —CH₂—CH₂—;    -   either    -   each of R₉ and R₁₀ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;    -   or    -   R₉ and R₁₀, taken together, are oxo or —CH₂—CH₂—;    -   either    -   each of R₁₁ and R₁₂ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;    -   or    -   R₁₁ and R₁₂, taken together, are oxo or —CR₁₅R₁₆—CR₁₇R₁₈—    -   wherein R₁₅, R₁₆, R₁₇ and R₁₈ are independently selected from        hydrogen and fluoro;    -   and    -   either    -   each of R₁₃ and R₁₄ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;    -   or    -   R₁₃ and R₁₄, taken together, are oxo or —CH₂—CH₂—;        or a pharmaceutically acceptable salt thereof.

In a second aspect, the invention relates to a compound of the formula

in which

-   -   either    -   X₁ is CR₁ or N;    -   X₃ is CR₃ or N;    -   X₄ is CR₄ or N;    -   X₅ is CR₅ or N;    -   wherein at least one of X₁, X₃, X₄ and X₅ is N and not more than        2 of X₁, X₃, X₄ and X₅ are N;    -   or    -   X₁ is CR₁ or N;    -   X₃ is CR₃, N or S;    -   X₄ is a bond;    -   X₅ is CR₅, N or S;    -   wherein at least one of X₁, X₃ and X₅ is N or S, not more than 2        of X₁, X₃ and X₅ are N and not more than 1 of X₃ and X₅ are S;    -   R₁ is hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy,        (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,        (C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,        (C₂₋₈)alkenyl, or (C₂₋₈)alkynyl;    -   R₂ is an aryl, heteroaryl or non-aromatic heterocyclyl group G₁,        which group G₁ is optionally substituted by 1, 2, 3 or 4        substituents independently selected from the group, consisting        of cyano, amino, amino-(C₁₋₈)alkyl,        N—(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl,        N,N-di(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, aminocarbonyl,        thiocarbamoyl, halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl,        hydroxy, oxo, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy,        (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,        (C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₃₋₈)cycloalkyl-(C₁₋₈)alkoxy,        (C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,        (C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,        (C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl, (C₂₋₈)alkynyl,        (C₂₋₈)alkenoxy, (C₂₋₈)alkynoxy and a (C₃₋₈)cycloalkyl, aryl,        heteroaryl or non-aromatic heterocyclyl group G₂, which group G₂        is optionally substituted by 1, 2, 3, or 4 substituents        independently selected from the group, consisting of cyano,        aminocarbonyl, halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl,        hydroxy, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio,        halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,        (C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,        (C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,        (C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl and        (C₂₋₈)alkynyl;    -   R₃ is hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy; halogen-(C₁₋₈)alkoxy,        (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,        (C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,        (C₂₋₈)alkenyl, or (C₂₋₈)alkynyl;    -   R₄ is hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy,        (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,        (C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,        (C₂₋₈)alkenyl, or (C₂₋₈)alkynyl;    -   R₅ is hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy,        (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,        (C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,        (C₂₋₈)alkenyl, or (C₂₋₈)alkynyl;    -   or    -   R₄ and R₅, taken together, are —C(H)═C(H)—C(H)═C(H)— or a        (C₁₋₈)alkylene group, in which (C₁₋₈)alkylene group 1 or 2 —CH₂—        ring members are optionally replaced with hetero ring members        independently selected from the group, consisting of —N(H)—,        —N[(C₁₋₈)alkyl]-, —O—, —S—, —S(═O)— or —S(═O)₂—;    -   R₆ is hydrogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl,        hydroxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,        mercapto-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,        amino-(C₁₋₈)alkyl, N—(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl,        N,N-di(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, (C₂₋₈)alkenyl, or        (C₂₋₈)alkynyl;    -   or    -   R₅ and R₆, taken together, are a (C₁₋₄)alkylene group, in which        (C₁₋₄)alkylene group 1 —CH₂— ring member is optionally replaced        with a hetero ring member independently selected from the group,        consisting of —N(H)—, —N[(C₁₋₄)alkyl]-, —O—, —S—, —S(═O)— or        —S(═O)₂—;    -   E₁ is —C(R₇)(R₈)—, or —C(R₇)(R₈)—C(R₉)(R₁₀)—;    -   E₂ is —C(R₁₁)(R₁₂)—, or —C(R₁₁)(R₁₂)—C(R₁₃)(R₁₄)—;    -   either    -   each of R₇ and R₈ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;    -   or    -   R₇ and R₈, taken together, are oxo or —CH₂—CH₂—;    -   either    -   each of R₉ and R₁₀ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;    -   or    -   R₉ and R₁₀, taken together, are oxo or —CH₂—CH₂—;    -   either    -   each of R₁₁ and R₁₂ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;    -   or    -   R₁₁ and R₁₂, taken together, are oxo or —CR₁₅R₁₆—CR₁₇R₁₈—    -   wherein R₁₅, R₁₆, R₁₇ and R₁₈ are independently selected from        hydrogen and fluoro;    -   and    -   either    -   each of R₁₃ and R₁₄ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;    -   or    -   R₁₃ and R₁₄, taken together, are oxo or —CH₂—CH₂—;        or a pharmaceutically acceptable salt thereof.

DEFINITIONS

Halogen denotes fluorine, chlorine, bromine or iodine.

A halogenated group or moiety, such as halogenalkyl, can be mono-, di-,tri-, poly- or per-halogenated.

An aryl group, ring or moiety is a naphthyl or phenyl group, ring ormoiety.

A heteroaryl group, ring or moiety is a monocyclic aromatic 5- or6-membered structure, in which structure 1, 2, 3 or 4 ring members arehetero ring members independently selected from the group, consisting ofa nitrogen ring member, an oxygen ring member and a sulfur ring member,such as furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl,pyridazinyl, pyrimidyl or pyridyl; or a bicyclic aromatic 9- or 10- ormembered structure, in which structure 1, 2, 3, 4 or 5 ring members arehetero ring members independently selected from the group, consisting ofa nitrogen ring member, an oxygen ring member and a sulfur ring member.The fused rings completing the bicyclic groups may contain only carbonatoms and may be saturated, partially saturated, or unsaturated.Heteroaryl groups which are bicyclic include at least one fully aromaticring but the other fused ring may be aromatic or non-aromatic. Examplesof bicyclic heteroaryl groups include, benzofuranyl, benzothiophenyl,imidazopyridinyl, indazolyl, indolyl, isoquinolinyl, pyrazolopyridinyl,quinolinyl, pyrrolopyrazinyl (in particular pyrrolo[2,3-b]pyrazinyl) andpyrrolopyridinyl (in particular pyrrolo[3,2-b]pyridinyl). The heteroarylradical may be bonded via a carbon atom or heteroatom.

A non-aromatic heterocyclyl group, ring or moiety is a non-aromatic 4-,5-, 6- or 7-membered cyclic structure, in which structure 1, 2 or 3 ringmembers are hetero ring members independently selected from the group,consisting of a nitrogen ring member, an oxygen ring member and a sulfurring member, such as azetidinyl, oxetanyl, pyrrolinyl, pyrrolidyl,tetrahydrofuryl, tetrahydrothienyl, piperidyl, piperazinyl,tetrahydropyranyl, morpholinyl or perhydroazepinyl.

Any non-cyclic carbon containing group or moiety with more than 1 carbonatom is straight-chain or branched.

The terms “alkoxy”, “alkenoxy” and “alkynoxy” respectively denote alkyl,alkenyl and alkynyl groups when linked by oxygen.

A “N,N-di(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl” group may contain two identicalor two different (C₁₋₄) moieties.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds of formula (I) as definedhereinbefore and pharmaceutical compositions thereof that may be usefulin the treatment or prevention of diseases, conditions and/or disordersmodulated by BACE inhibition.

On account of one or more than one asymmetrical carbon atom, which maybe present in a compound of the formula I, a corresponding compound ofthe formula I may exist in pure optically active form or in the form ofa mixture of optical isomers, e. g. in the form of a racemic mixture.All of such pure optical isomers and all of their mixtures, includingthe racemic mixtures, are part of the present invention.

In one embodiment, the invention therefore relates to a compound of theformula

in which

-   -   E₁, E₂, R₂, R₆, X₁, X₃, X₄ and X₅ are as defined hereinbefore in        relation to the formula I, or a pharmaceutically acceptable salt        thereof.

In one embodiment, the invention therefore relates to a compound of theformula

in which

-   -   E₁, E₂, R₂, R₆, X₁, X₃, X₄ and X₅ are as defined hereinbefore in        relation to the formula I, or a pharmaceutically acceptable salt        thereof.

In one embodiment, there is provided a compound of the Examples as anisolated stereoisomer wherein the compound has one stereocenter and thestereoisomer is in the R configuration.

In one embodiment, there is provided a compound of the Examples as anisolated stereoisomer wherein the compound has one stereocenter and thestereoisomer is in the S configuration.

In one embodiment, there is provided a compound of the Examples as anisolated stereoisomer wherein the compound has two stereocenters and thestereoisomer is in the R R configuration.

In one embodiment, there is provided a compound of the Examples as anisolated stereoisomer wherein the compound has two stereocenters and thestereoisomer is in the R S configuration.

In one embodiment, there is provided a compound of the Examples as anisolated stereoisomer wherein the compound has two stereocenters and thestereoisomer is in the S R configuration.

In one embodiment, there is provided a compound of the Examples as anisolated stereoisomer wherein the compound has two stereocenters and thestereoisomer is in the S S configuration.

In one embodiment, there is provided a compound of the Examples, whereinthe compound has one or two stereocenters, as a racemic mixture.

As used herein, the term “isomers” refers to different compounds thathave the same molecular formula but differ in arrangement andconfiguration of the atoms. Also as used herein, the term “an opticalisomer” or “a stereoisomer” refers to any of the various stereo isomericconfigurations which may exist for a given compound of the presentinvention and includes geometric isomers. It is understood that asubstituent may be attached at a chiral center of a carbon atom.Therefore, the invention includes enantiomers, diastereomers orracemates of the compound. “Enantiomers” are a pair of stereoisomersthat are non-superimposable mirror images of each other. A 1:1 mixtureof a pair of enantiomers is a “racemic” mixture. The term is used todesignate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R-S system. When a compound is apure enantiomer the stereochemistry at each chiral carbon may bespecified by either R or S. Resolved compounds whose absoluteconfiguration is unknown can be designated (+) or (−) depending on thedirection (dextro- or levorotatory) which they rotate plane polarizedlight at the wavelength of the sodium D line. Certain of the compoundsdescribed herein contain one or more asymmetric centers or axes and maythus give rise to enantiomers, diastereomers, and other stereoisomericforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)-. The present invention is meant to include all such possibleisomers, including racemic mixtures, optically pure forms andintermediate mixtures. Optically active (R)- and (S)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. If the compound contains a double bond, thesubstituent may be E or Z configuration. If the compound contains adisubstituted cycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration.

A compound of the formula I may exist in tautomeric form. All suchtautomers are part of the present invention.

A compound of the formula I may exist in free form or in salt form, forexample a basic compound in acid addition salt form or an acidiccompound in the form of a salt with a base. All of such free compoundsand salts are part of the present invention.

In one embodiment, the invention relates to a compound of the formula I,Ia, Ib, Ic, Id or Ie in free form. In another embodiment, the inventionrelates to a compound of the formula I, la, Ib, Ic, Id or Ie as definedherein, in salt form. In another embodiment, the invention relates to acompound of the formula I, Ia, Ib, Ic, Id or Ie as defined herein, inacid addition salt form. In a further embodiment, the invention relatesto a compound of the formula I, Ia, Ib, Ic, Id or Ie as defined herein,in pharmaceutically acceptable salt form. In yet a further embodiment,the invention relates to a compound of the formula I, Ia, Ib, Ic, Id orIe as defined herein, in hydrochloride salt form. In yet a furtherembodiment, the invention relates to any one of the compounds of theExamples in free form. In yet a further embodiment, the inventionrelates to any one of the compounds of the Examples in salt form. In yeta further embodiment, the invention relates to any one of the compoundsof the Examples in acid addition salt form. In yet a further embodiment,the invention relates to any one of the compounds of the Examples inpharmaceutically acceptable salt form. In yet a further embodiment, theinvention relates to any one of the compounds of the Examples inhydrochloride salt form.

As used herein, the terms “salt” or “salts” refers to an acid additionor base addition salt of a compound of the invention. “Salts” include inparticular “pharmaceutically acceptable salts”. The term“pharmaceutically acceptable salts” refers to salts that retain thebiological effectiveness and properties of the compounds of thisinvention and, which typically are not biologically or otherwiseundesirable. In many cases, the compounds of the present invention arecapable of forming acid and/or base salts by virtue of the presence ofamino and/or carboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfornate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts. Inorganic acids from which salts can be derivedinclude, for example, hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid and phosphoric acid. Organic acids from which saltscan be derived include, for example, acetic acid, propionic acid,glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid,fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid andsulfosalicylic acid. Pharmaceutically acceptable base addition salts canbe formed with inorganic and organic bases. Inorganic bases from whichsalts can be derived include, for example, ammonium salts and metalsfrom columns I to XII of the periodic table. In certain embodiments, thesalts are derived from sodium, potassium, ammonium, calcium, magnesium,iron, silver, zinc, and copper; particularly suitable salts includeammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins. Certain organic amines include isopropylamine,benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine,piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a parent compound, a basic or acidic moiety, byconventional chemical methods. Generally, such salts can be prepared byreacting free acid forms of these compounds with a stoichiometric amountof the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate,bicarbonate or the like), or by reacting free base forms of thesecompounds with a stoichiometric amount of the appropriate acid. Suchreactions are typically carried out in water or in an organic solvent,or in a mixture of the two. Generally, use of non-aqueous media likeether, ethyl acetate, ethanol, isopropanol, or acetonitrile isdesirable, where practicable. Lists of additional suitable salts can befound, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., MackPublishing Company, Easton, Pa., (1985); and in “Handbook ofPharmaceutical Salts: Properties, Selection, and Use” by Stahl andWermuth (Wiley-VCH, Weinheim, Germany, 2002).

When both a basic group and an acid group are present in the samemolecule, the compounds of the present invention may also form internalsalts, e.g., zwitterionic molecules.

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization. The compounds of thepresent invention may inherently or by design form solvates withpharmaceutically acceptable solvents (including water); therefore, it isintended that the invention embrace both solvated and unsolvated forms.The term “solvate” refers to a molecular complex of a compound of thepresent invention (including pharmaceutically acceptable salts thereof)with one or more solvent molecules. Such solvent molecules are thosecommonly used in the pharmaceutical art, which are known to be innocuousto the recipient, e.g., water, ethanol, and the like. The term “hydrate”refers to the complex where the solvent molecule is water.

The compounds of the present invention, including salts, hydrates andsolvates thereof, may inherently or by design form polymorphs. All suchpolymorphs are part of the present invention.

The present invention includes all pharmaceutically acceptableisotope-labeled compounds of the formula I, wherein one or more than oneatom is/are replaced by one or more than one atom having the same atomicnumber as, but an atomic mass different from, the one(s) usually foundin nature. Examples of such isotopes are those of carbon, such as ¹¹C,¹³C or ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F, bromine, suchas ⁷⁶Br, hydrogen, such as ²H or ³H, iodine, such as ¹²³I, ¹²⁴I, ¹²⁵I or¹³¹I, nitrogen, such as ¹³N or ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O or ¹⁸O,phosphorus, such as ³²P, or sulphur, such as ³⁵S. An isotope-labeledcompound of the formula I can be prepared by a process analogous tothose described in the Examples or by a conventional technique known tothose skilled in the art using an appropriate isotopically-labeledreagent or starting material. The incorporation of a heavier isotope,such as ²H (deuterium or D), may provide greater metabolic stability toa compound of the formula I, which may result in, for example, anincreased in vivo-half-life of the compound or in reduced dosagerequirements. Certain isotope-labeled compounds of the formula I, forexample those incorporating a radioactive isotope, such as ³H or ¹⁴C,may be used in drug or substrate-tissue distribution studies. Compoundsof the formula I with a positron emitting isotope, such as ¹¹C, ¹⁸F, ¹³Nor ¹⁵O, may be useful in positron emission tomography (PET) or singlephoton emission computed tomography (SPECT) studies, e. g. to examinesubstrate-receptor occupancies.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Compounds of the invention, i.e. compounds of formula I, Ia, Ib, Ic, Idor Ie that contain groups capable of acting as donors and/or acceptorsfor hydrogen bonds may be capable of forming co-crystals with suitableco-crystal formers. These co-crystals may be prepared from compounds offormula I, Ia, Ib, Ic, Id or Ie by known co-crystal forming procedures.Such procedures include grinding, heating, co-subliming, co-melting, orcontacting in solution compounds of formula I, Ia, Ib, Ic, Id or Ie withthe co-crystal former under crystallization conditions and isolatingco-crystals thereby formed. Suitable co-crystal formers include thosedescribed in WO 2004/078163. Hence the invention further providesco-crystals comprising a compound of formula I, Ia, Ib, Ic, Id or Ie.

In certain embodiments, the invention relates to a compound of theformula I, la, Ib, Ic, Id or Ie, or a pharmaceutically acceptable saltthereof, in which:

(1) X₁ is CR₁ or N;

-   -   X₃ is CR₃ or N;    -   X₄ is CR₄ or N;    -   X₅ is CR₅;    -   wherein at least one of X₁, X₃ and X₄ is N and not more than 2        of X₁, X₃ and X₄ are N.        (2) X₁ is CH or N;    -   X₃ is CH or N;    -   X₄ is CR₄ or N;    -   X₅ is CR₅;    -   wherein one and not more than one of X₁, X₃ and X₄ is N;        (3) X₁ is N; X₃ is CR₃; X₄ is CR₄; and X₅ is CR₅.        (4) X₁ is CR₁; X₃ is N; X₄ is CR₄; and X₅ is CR₅.        (5) X₁ is CR₁; X₃ is CR₃; X₄ is N; and X₅ is CR₅.        (6) X₁ is CR₁; X₃ is CR₃; X₄ is CR₄; and X₅ is N.        (7) X₁ is N; X₃ is N; X₄ is CR₄; and X₅ is CR₅.        (8) X₁ is N; X₃ is CR₃; X₄ is N; and X₅ is CR₅.        (9) X₁ is N; X₃ is CR₃; X₄ is CR₄; and X₅ is N.        (10) X₁ is CR₁; X₃ is N; X₄ is N; and X₅ is CR₅.        (11) X₁ is CR₁; X₃ is N; X₄ is CR₄; and X₅ is N.        (12) X₁ is CR₁; X₃ is CR₃; X₄ is N; and X₅ is N.        (13) R₁ is hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy,        (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,        (C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,        (C₂₋₈)alkenyl, or (C₂₋₈)alkynyl.        (14) R₁ is hydrogen, cyano, halogen, (C₁₋₄)alkyl,        halogen-(C₁₋₄)alkyl, (C₁₋₄)alkoxy, or halogen-(C₁₋₄)alkoxy.        (15) R₁ is hydrogen.        (16) R₂ is an aryl or heteroaryl group G₁, which group G₁ is        optionally substituted by 1, 2, 3 or 4 substituents        independently selected from the group, consisting of cyano,        amino, amino-(C₁₋₆)alkyl, (C₁₋₆)alkyl-amino-(C₁₋₆)alkyl,        di(C₁₋₄)alkyl-amino-(C₁₋₆)alkyl, aminocarbonyl, thiocarbamoyl,        halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl, hydroxy, oxo,        (C₁₋₈)alkoxy, halogen-(C₁₋₆)alkoxy, (C₁₋₆)alkylthio,        halogen-(C₁₋₆)alkylthio, (C₁₋₆)alkoxy-(C₁₋₆)alkyl,        (C₃₋₆)cycloalkyl-(C₁₋₆)alkoxy, (C₁₋₆)alkoxy-(C₁₋₈)alkoxy,        (C₁₋₆)alkoxy-(C₁₋₆)alkylthio, (C₁₋₆)alkylthio-(C₁₋₆)alkyl,        (C₁₋₆)alkylthio-(C₁₋₈)alkoxy, (C₁₋₆)alkylthio-(C₁₋₈)alkylthio,        (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₂₋₆)alkenoxy, (C₂₋₆)alkynoxy and        a (C₃₋₈)cycloalkyl, aryl, heteroaryl or non-aromatic        heterocyclyl group G₂, which group G₂ is optionally substituted        by 1 to 4 substituents independently selected from the group,        consisting of cyano, aminocarbonyl, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, hydroxy, (C₁₋₆)alkoxy,        halogen-(C₁₋₆)alkoxy, (C₁₋₆)alkylthio, halogen-(C₁₋₆)alkylthio,        (C₁₋₆)alkoxy-(C₁₋₆)alkyl, (C₁₋₆)alkoxy-(C₁₋₈)alkoxy,        (C₁₋₆)alkoxy-(C₁₋₈)alkylthio, (C₁₋₆)alkylthio-(C₁₋₈)alkyl,        (C₁₋₆)alkylthio-(C₁₋₆)alkoxy, (C₁₋₈)alkylthio-(C₁₋₆)alkylthio,        (C₂₋₆)alkenyl and (C₂-8)alkynyl.        (17) R₂ is a heteroaryl group, which is optionally substituted        by 1, 2, 3 or 4 substituents independently selected from the        group, consisting of cyano, amino, amino-(C₁₋₆)alkyl,        (C₁₋₆)alkyl-amino-(C₁₋₆)alkyl, di(C₁₋₄)alkyl-amino-(C₁₋₆)alkyl,        aminocarbonyl, thiocarbamoyl, halogen, (C₁₋₆)alkyl,        halogen-(C₁₋₆)alkyl, hydroxy, oxo, (C₁₋₆)alkoxy,        halogen-(C₁₋₆)alkoxy, (C₁₋₆)alkylthio, halogen-(C₁₋₆)alkylthio,        (C₁₋₆)alkoxy-(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl-(C₁₋₆)alkoxy,        (C₁₋₆)alkoxy-(C₁₋₆)alkoxy, (C₁₋₆)alkoxy-(C₁₋₆)alkylthio,        (C₁₋₆)alkylthio-(C₁₋₆)alkyl, (C₁₋₆)alkylthio-(C₁₋₆)alkoxy,        (C₁₋₆)alkylthio-(C₁₋₆)alkylthio, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,        (C₂₋₆)alkenoxy, (C₂₋₆)alkynoxy.        (18) R₂ is a 9- or 10- or membered bicyclic heteroaryl group,        which is optionally substituted by 1, 2, 3 or 4 substituents        independently selected from the group, consisting of cyano,        amino, amino-(C₁₋₆)alkyl, (C₁₋₆)alkyl-amino-(C₁₋₆)alkyl,        di(C₁₋₄)alkyl-amino-(C₁₋₆)alkyl, aminocarbonyl, thiocarbamoyl,        halogen, (C₁₋₆)alkyl, halogen-(C₁₋₆)alkyl, hydroxy, oxo,        (C₁₋₆)alkoxy, halogen-(C₁₋₆)alkoxy, (C₁₋₆)alkylthio,        halogen-(C₁₋₆)alkylthio, (C₁₋₆)alkoxy-(C₁₋₆)alkyl,        (C₃₋₆)cycloalkyl-(C₁₋₆)alkoxy, (C₁₋₆)alkoxy-(C₁₋₆)alkoxy,        (C₁₋₆)alkoxy-(C₁₋₆)alkylthio, (C₁₋₆)alkylthio-(C₁₋₆)alkyl,        (C₁₋₆)alkylthio-(C₁₋₆)alkoxy, (C₁₋₆)alkylthio-(C₁₋₆)alkylthio,        (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₂₋₆)alkenoxy, (C₂₋₆)alkynoxy.        (19) R₂ is a 9- or 10- or membered bicyclic heteroaryl group,        which is optionally substituted by 1, 2, 3 or 4 substituents        independently selected from the group, consisting of cyano,        amino, halogen, (C₁₋₄)alkyl, difluoromethyl, trifluoromethyl,        hydroxy, oxo, (C₁₋₄)alkoxy, (C₁₋₄)alkoxy-(C₁₋₄ alkyl and        halogen-(C₁₋₄)alkoxy.        (20) R₂ is a 9-membered bicyclic heteroaryl group in which        structure 1, 2 or 3 ring members are nitrogen ring members,        which is optionally substituted by 1, 2, 3 or 4 substituents        independently selected from the group, consisting of cyano,        amino, amino-(C₁₋₆)alkyl, (C₁₋₆)alkyl-amino-(C₁₋₆)alkyl,        di(C₁₋₄)alkyl-amino-(C₁₋₆)alkyl, aminocarbonyl, thiocarbamoyl,        halogen, (C₁₋₆)alkyl, halogen-(C₁₋₆)alkyl, hydroxy, oxo,        (C₁₋₆)alkoxy, halogen-(C₁₋₆)alkoxy, (C₁₋₆)alkylthio,        halogen-(C₁₋₆)alkylthio, (C₁₋₆)alkoxy-(C₁₋₆)alkyl,        (C₃₋₆)cycloalkyl-(C₁₋₆)alkoxy, (C₁₋₆)alkoxy-(C₁₋₆)alkoxy,        (C₁₋₆)alkoxy-(C₁₋₆)alkylthio, (C₁₋₆)alkylthio-(C₁₋₆)alkyl,        (C₁₋₆)alkylthio-(C₁₋₆)alkoxy, (C₁₋₆)alkylthio-(C₁₋₆)alkylthio,        (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₂₋₆)alkenoxy, (C₂-6)alkynoxy.        (21) R₂ is a 9-membered bicyclic heteroaryl group in which        structure 1, 2 or 3 ring members are nitrogen ring members,        which is optionally substituted by 1, 2, 3 or 4 substituents        independently selected from the group, consisting of cyano,        amino, halogen, (C₁₋₄)alkyl, difluoromethyl, trifluoromethyl,        hydroxy, oxo, (C₁₋₄)alkoxy, (C₁₋₄)alkoxy-(C₁₋₄)alkyl and        halogen-(C₁₋₄)alkoxy.        (22) R₂ is a 5- or 6-membered heteroaryl group in which        structure 1, 2, 3, or 4 ring members are hetero ring members        independently selected from the group consisting of a nitrogen        ring member, an oxygen ring member and a sulfur ring member,        which group is optionally substituted by 1, 2, 3 or 4        substituents independently selected from the group, consisting        of cyano, amino, aminocarbonyl, thiocarbamoyl, halogen,        (C₁₋₄)alkyl, halogen-(C₁₋₄ alkyl, hydroxy, oxo, (C₁₋₄)alkoxy,        halogen-(C₁₋₄ alkoxy, (C₁₋₄)alkylthio, halogen-(C₁₋₄ alkylthio,        (C₁₋₄)alkoxy-(C₁₋₄ alkyl, (C₃₋₄)cycloalkyl-(C₁₋₄)alkoxy, (C₁₋₄        alkoxy-(C₁₋₄)alkoxy, (C₁₋₄)alkoxy-(C₁₋₄)alkylthio,        (C₁₋₄)alkylthio-(C₁₋₄)alkyl, (C₁₋₄)alkylthio-(C₁₋₄)alkoxy,        (C₁₋₄)alkylthio-(C₁₋₄)alkylthio, (C₂₋₄)alkenyl, (C₂₋₄)alkynyl,        (C₂₋₄)alkenoxy, and (C₂₋₄)alkynoxy.        (23) R₂ is a 6-membered heteroaryl group in which structure 1,        2, 3, or 4 ring members are hetero ring members independently        selected from the group consisting of a nitrogen ring member, an        oxygen ring member and a sulfur ring member, which group is        optionally substituted by 1, 2, 3 or 4 substituents        independently selected from the group, consisting of cyano,        amino, aminocarbonyl, thiocarbamoyl, halogen, (C₁₋₄)alkyl,        halogen-(C₁₋₄)alkyl, hydroxy, oxo, (C₁₋₄)alkoxy, halogen-(C₁₋₄        alkoxy, (C₁₋₄)alkylthio, halogen-(C₁₋₄ alkylthio,        (C₁₋₄)alkoxy-(C₁₋₄)alkyl, (C₃₋₄)cycloalkyl-(C₁₋₄)alkoxy,        (C₁₋₄)alkoxy-(C₁₋₄)alkoxy, (C₁₋₄)alkoxy-(C₁₋₄)alkylthio,        (C₁₋₄)alkylthio-(C₁₋₄)alkyl, (C₁₋₄)alkylthio-(C₁₋₄)alkoxy,        (C₁₋₄)alkylthio-(C₁₋₄)alkylthio, (C₂₋₄)alkenyl, (C₂₋₄)alkynyl,        (C₂₋₄)alkenoxy, and (C₂₋₄)alkynoxy.        (24) R₂ is a 6-membered heteroaryl group in which structure 1,        2, 3, or 4 ring members are hetero ring members independently        selected from the group consisting of a nitrogen ring member, an        oxygen ring member and a sulfur ring member, which group is        optionally substituted by 1, 2, 3 or 4 substituents        independently selected from the group, consisting of cyano,        amino, halogen, (C₁₋₄)alkyl, halogen-(C₁₋₄ alkyl, hydroxy, oxo,        (C₁₋₄)alkoxy and halogen-(C₁₋₄)alkoxy.        (25) R₂ is a pyridyl or pyrazinyl group which is optionally        substituted by 1, 2 or 3 substituents independently selected        from the group, consisting of cyano, amino, aminocarbonyl,        thiocarbamoyl, halogen, (C₁₋₄)alkyl, halogen-(C₁₋₄ alkyl,        hydroxy, oxo, (C₁₋₄)alkoxy, halogen-(C₁₋₄)alkoxy,        (C₁₋₄)alkylthio, halogen-(C₁₋₄ alkylthio,        (C₁₋₄)alkoxy-(C₁₋₄)alkyl, (C₃₋₄)cycloalkyl-(C₁₋₄)alkoxy,        (C₁₋₄)alkoxy-(C₁₋₄)alkoxy, (C₁₋₄)alkoxy-(C₁₋₄)alkylthio,        (C₁₋₄)alkylthio-(C₁₋₄)alkyl, (C₁₋₄)alkylthio-(C₁₋₄)alkoxy,        (C₁₋₄)alkylthio-(C₁₋₄)alkylthio, (C₂₋₄)alkenyl, (C₂₋₄)alkynyl,        (C₂₋₄)alkenoxy, and (C₂₋₄)alkynoxy.        (26) R₂ is a pyridyl or pyrazinyl group which is optionally        substituted by 1, 2 or 3 substituents independently selected        from the group, consisting of cyano, amino, halogen,        (C₁₋₄)alkyl, halogen-(C₁₋₄ alkyl, hydroxy, oxo, (C₁₋₄)alkoxy and        halogen-(C₁₋₄ alkoxy.        (27) R₂ is a pyridin-2-yl or pyrazin-2-yl group which is        optionally substituted by 1, 2 or 3 substituents independently        selected from the group, consisting of cyano, amino,        aminocarbonyl, thiocarbamoyl, halogen, (C₁₋₄)alkyl,        halogen-(C₁₋₄)alkyl, hydroxy, oxo, (C₁₋₄)alkoxy, halogen-(C₁₋₄        alkoxy, (C₁₋₄)alkylthio, halogen-(C₁₋₄ alkylthio,        (C₁₋₄)alkoxy-(C₁₋₄)alkyl, (C₃₋₄)cycloalkyl-(C₁₋₄)alkoxy,        (C₁₋₄)alkoxy-(C₁₋₄)alkoxy, (C₁₋₄)alkoxy-(C₁₋₄)alkylthio,        (C₁₋₄)alkylthio-(C₁₋₄)alkyl, (C₁₋₄)alkylthio-(C₁₋₄)alkoxy,        (C₁₋₄)alkylthio-(C₁₋₄)alkylthio, (C₂₋₄)alkenyl, (C₂₋₄)alkynyl,        (C₂₋₄)alkenoxy, and (C₂₋₄)alkynoxy.        (28) R₂ is a pyridin-2-yl or pyrazin-2-yl group which is        optionally substituted by 1, 2 or 3 substituents independently        selected from the group, consisting of cyano, amino, halogen,        (C₁₋₄)alkyl, halogen-(C₁₋₄)alkyl, hydroxy, oxo, (C₁₋₄)alkoxy and        halogen-(C₁₋₄ alkoxy.        (29) R₂ is a pyridin-2-yl or pyrazin-2-yl group which is        optionally substituted by 1 or 2 substituents independently        selected from the group, consisting of cyano, amino, fluoro,        bromo, chloro, hydroxyl, oxo, methyl, fluoromethyl,        difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,        difluoromethoxy and trifluromethoxy.        (30) R₂ is a pyridyl or pyrazinyl group which is substituted by        1, 2 or 3 substituents and wherein one of the substituents is        located at the para position of the pyridyl or pyrazinyl group        relative to the amide linker and wherein the substituents are        independently selected from the group, consisting of cyano,        amino, aminocarbonyl, thiocarbamoyl, halogen, (C₁₋₄)alkyl,        halogen-(C₁₋₄)alkyl, hydroxy, oxo, (C₁₋₄)alkoxy, halogen-(C₁₋₄        alkoxy, (C₁₋₄)alkylthio, halogen-(C₁₋₄ alkylthio,        (C₁₋₄)alkoxy-(C₁₋₄)alkyl, (C₃₋₄)cycloalkyl-(C₁₋₄)alkoxy,        (C₁₋₄)alkoxy-(C₁₋₄)alkoxy, (C₁₋₄)alkoxy-(C₁₋₄)alkylthio,        (C₁₋₄)alkylthio-(C₁₋₄)alkyl, (C₁₋₄)alkylthio-(C₁₋₄)alkoxy,        (C₁₋₄)alkylthio-(C₁₋₄)alkylthio, (C₂₋₄)alkenyl, (C₂₋₄)alkynyl,        (C₂₋₄)alkenoxy, and (C₂₋₄)alkynoxy.        (31) R₂ is a pyridyl or pyrazinyl group which is substituted by        1, 2 or 3 substituents and wherein one of the substituents is        located at the para position of the pyridyl or pyrazinyl group        relative to the amide linker and wherein the substituents are        independently selected from the group, consisting of cyano,        amino, halogen, (C₁₋₄)alkyl, halogen-(C₁₋₄)alkyl, hydroxy, oxo,        (C₁₋₄)alkoxy and halogen-(C₁₋₄ alkoxy.        (32) R₂ is a pyridin-2-yl or pyrazin-2-yl group which is        substituted by 1, 2 or 3 substituents and wherein one of the        substituents is located at the para position of the pyridin-2-yl        or pyrazin-2-yl group relative to the amide linker and wherein        the substituents are independently selected from the group,        consisting of cyano, amino, halogen, (C₁₋₄)alkyl,        halogen-(C₁₋₄)alkyl, hydroxy, oxo, (C₁₋₄)alkoxy and        halogen-(C₁₋₄ alkoxy.        (33) R₂ is a pyridyl or pyrazinyl group which is substituted by        2 or 3 substituents and wherein one of the substituents is        located at the para position and one of the substituents is        located at the ortho position of the pyridyl or pyrazinyl group        relative to the amide linker and wherein the substituents are        independently selected from the group, consisting of cyano,        amino, aminocarbonyl, thiocarbamoyl, halogen, (C₁₋₄)alkyl,        halogen-(C₁₋₄)alkyl, hydroxy, oxo, (C₁₋₄)alkoxy, halogen-(C₁₋₄        alkoxy, (C₁₋₄)alkylthio, halogen-(C₁₋₄ alkylthio,        (C₁₋₄)alkoxy-(C₁₋₄)alkyl, (C₃₋₄)cycloalkyl-(C₁₋₄)alkoxy,        (C₁₋₄)alkoxy-(C₁₋₄)alkoxy, (C₁₋₄)alkoxy-(C₁₋₄)alkylthio,        (C₁₋₄)alkylthio-(C₁₋₄)alkyl, (C₁₋₄)alkylthio-(C₁₋₄)alkoxy,        (C₁₋₄)alkylthio-(C₁₋₄)alkylthio, (C₂₋₄)alkenyl, (C₂₋₄)alkynyl,        (C₂₋₄)alkenoxy, and (C₂₋₄)alkynoxy.        (34) R₂ is a pyridyl or pyrazinyl group which is substituted by        2 or 3 substituents and wherein one of the substituents is        located at the para position and one of the substituents is        located at the ortho position of the pyridyl or pyrazinyl group        relative to the amide linker and wherein the substituents are        independently selected from the group, consisting of cyano,        amino, halogen, (C₁₋₄)alkyl, halogen-(C₁₋₄)alkyl, hydroxy, oxo,        (C₁₋₄)alkoxy and halogen-(C₁₋₄ alkoxy.        (35) R₂ is a pyridin-2-yl or pyrazin-2-yl group which is        substituted by 2 substituents and wherein one of the        substituents is located at the para position and one of the        substituents is located at the ortho position of the        pyridin-2-yl or pyrazin-2-yl group relative to the amide linker        and wherein the substituents are independently selected from the        group, consisting of cyano, amino, halogen, (C₁₋₄)alkyl,        halogen-(C₁₋₄)alkyl, hydroxy, oxo, (C₁₋₄)alkoxy and        halogen-(C₁₋₄)alkoxy.        (36) R₂ is a pyridin-2-yl or pyrazin-2-yl group which is        substituted by 2 substituents and wherein one of the        substituents is located at the para position and one of the        substituents is located at the ortho position of the        pyridin-2-yl or pyrazin-2-yl group relative to the amide linker        and wherein the substituents are independently selected from the        group, consisting of cyano, amino, fluoro, bromo, chloro,        hydroxyl, oxo, methyl, fluoromethyl, difluoromethyl,        trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy and        trifluromethoxy.        (37) R₃ is hydrogen, cyano, halogen, (C₁₋₄)alkyl,        halogen-(C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen-(C₁₋₄)alkoxy,        (C₁₋₄)alkylthio, halogen-(C₁₋₄ alkylthio,        (C₁₋₄)alkoxy-(C₁₋₄)alkyl, (C₁₋₄)alkoxy-(C₁₋₄)alkoxy,        (C₁₋₄)alkoxy-(C₁₋₄)alkylthio, (C₁₋₄)alkylthio-(C₁₋₄)alkyl,        (C₁₋₄)alkylthio-(C₁₋₄)alkoxy, (C₁₋₄)alkylthio-(C₁₋₄)alkylthio,        (C₂₋₄)alkenyl, or (C₂₋₄)alkynyl.        (38) R₃ is hydrogen, cyano, halogen, (C₁₋₄)alkyl,        halogen-(C₁₋₄)alkyl, (C₁₋₄)alkoxy, or halogen-(C₁₋₄)alkoxy.        (39) R₃ is hydrogen.        (40) R₄ is hydrogen, cyano, halogen, (C₁₋₄)alkyl,        halogen-(C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen-(C₁₋₄)alkoxy,        (C₁₋₄)alkylthio, halogen-(C₁₋₄ alkylthio,        (C₁₋₄)alkoxy-(C₁₋₄)alkyl, (C₁₋₄)alkoxy-(C₁₋₄)alkoxy,        (C₁₋₄)alkoxy-(C₁₋₄)alkylthio, (C₁₋₄)alkylthio-(C₁₋₄)alkyl,        (C₁₋₄)alkylthio-(C₁₋₄)alkoxy, (C₁₋₄)alkylthio-(C₁₋₄)alkylthio,        (C₂₋₄)alkenyl, or (C₂₋₄)alkynyl.        (41) R₄ is hydrogen, cyano, halogen, (C₁₋₄)alkyl, halogen-(C₁₋₄        alkyl, (C₁₋₄)alkoxy, or halogen-(C₁₋₄)alkoxy.        (42) R₄ is hydrogen or halogen.        (43) R₄ is hydrogen.        (44) R₄ is fluoro.        (45) R₅ is hydrogen, cyano, halogen, (C₁₋₄)alkyl, halogen-(C₁₋₄        alkyl, (C₁₋₄)alkoxy, halogen-(C₁₋₄)alkoxy, (C₁₋₄)alkylthio,        halogen-(C₁₋₄ alkylthio, (C₁₋₄ alkoxy-(C₁₋₄)alkyl,        (C₁₋₄)alkoxy-(C₁₋₄)alkoxy, (C₁₋₄)alkoxy-(C₁₋₄)alkylthio,        (C₁₋₄)alkylthio-(C₁₋₄)alkyl, (C₁₋₄)alkylthio-(C₁₋₄)alkoxy,        (C₁₋₄)alkylthio-(C₁₋₄)alkylthio, (C₂₋₄)alkenyl, or        (C₂₋₄)alkynyl.        (46) R₅ is hydrogen, cyano, halogen, (C₁₋₄)alkyl, halogen-(C₁₋₄        alkyl, (C₁₋₄)alkoxy, or halogen-(C₁₋₄)alkoxy.        (47) R₅ is hydrogen or halogen.        (48) R₅ is hydrogen or fluoro.        (49) R₅ is halogen.        (50) R₅ is fluoro;        (51) R₅ is hydrogen.        (52) R₆ is hydrogen, (C₁₋₄)alkyl, halogen-(C₁₋₄ alkyl,        hydroxy-(C₁₋₄)alkyl, (C₁₋₄)alkoxy-(C₁₋₄)alkyl,        mercapto-(C₁₋₄)alkyl, (C₁₋₄)alkylthio-(C₁₋₄)alkyl,        amino-(C₁₋₄)alkyl, (C₁₋₄)alkyl-amino-(C₁₋₄)alkyl,        di(C₁₋₄)alkyl-amino-(C₁₋₄)alkyl, (C₂₋₄)alkenyl, or        (C₂₋₄)alkynyl.        (53) R₆ is (C₁₋₄)alkyl, halogen-(C₁₋₄ alkyl,        hydroxy-(C₁₋₄)alkyl, (C₁₋₄)alkoxy-(C₁₋₄)alkyl, mercapto-(C₁₋₄        alkyl, (C₁₋₄)alkylthio-(C₁₋₄)alkyl, amino-(C₁₋₄)alkyl,        (C₁₋₄)alkyl-amino-(C₁₋₄)alkyl, di(C₁₋₄)alkyl-amino-(C₁₋₄)alkyl,        (C₂₋₄)alkenyl, or (C₂₋₄)alkynyl.        (54) R₆ is (C₁₋₃)alkyl or halogen-(C₁₋₃)alkyl.        (55) R₆ is (C₁₋₃)alkyl or fluoro-(C₁₋₃)alkyl.        (56) R₆ is methyl, fluoromethyl, difluoromethyl or        trifluoromethyl.        (57) E₁ is —C(R₇)(R₈)—, or —C(R₇)(R₈)—C(R₉)(R₁₀)—.        (58) E₁ is —C(R₇)(R₈)—.        (59) E₂ is —C(R₁₁)(R₁₂)—, or —C(R₁₁)(R₁₂)—C(R₁₃)(R₁₄)—.        (60) E₂ is —C(R₁₁)(R₁₂)—.        (61) either        each of R₇ and R₈ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;        or        R₇ and R₈, taken together, are oxo or —CH₂—CH₂—.        (62) either        each of R₇ and R₈ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₃)alkyl and        halogen-(C₁₋₃)alkyl;        or        R₇ and R₈, taken together, are oxo or —CH₂—CH₂—.        (63) either        each of R₇ and R₈ is hydrogen;        or        R₇ and R₈, taken together, are oxo.        (64) each of R₇ and R₈ is hydrogen.        (65) either        each of R₉ and R₁₀ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;        or        R₉ and R₁₀, taken together, are oxo or —CH₂—CH₂—.        (66) each of R₉ and R₁₀ is hydrogen.        (67) either        each of R₁₁ and R₁₂ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;        or        R₁₁ and R₁₂, taken together, are oxo or —CH₂—CH₂—;        (68) each of R₁₁ and R₁₂ is independently selected from the        group, consisting of hydrogen, halogen, (C₁₋₈)alkyl and        halogen-(C₁₋₈)alkyl;        each of R₁₁ and R₁₂ is independently selected from the group,        consisting of hydrogen, (C₁₋₈)alkyl and halogen-(C₁₋₈)alkyl;        (69) either        each of R₁₁ and R₁₂ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₃)alkyl and        halogen-(C₁₋₃)alkyl;        or        R₁₁ and R₁₂, taken together, are oxo or —CR₁₅R₁₆—CR₁₇R₁₈—        wherein R₁₆, R₁₇, R₁₈ and R₁₉ are independently selected from        hydrogen and fluoro;        (70) either        each of R₁₁ and R₁₂ is independently selected from the group,        consisting of hydrogen, (C₁₋₃)alkyl and halogen-(C₁₋₃)alkyl;        or        R₁₁ and R₁₂, taken together, are oxo;        (71) either        each of R₁₁ and R₁₂ is independently selected from the group,        consisting of hydrogen, methyl and ethyl;        or        R₁₁ and R₁₂, taken together, are oxo;        (72) each of R₁₁ and R₁₂ is independently selected from the        group, consisting of hydrogen, (C₁₋₃)alkyl and        halogen-(C₁₋₃)alkyl;        (73) R₁₁ is (C₁₋₈)alkyl, and R₁₂ is halogen-(C₁₋₈)alkyl;        (74) R₁₁ is (C₁₋₃)alkyl, and R₁₂ is halogen-(C₁₋₃)alkyl;        (75) each of R₁₁ and R₁₂ is independently selected from the        group, consisting of hydrogen, (C₁₋₃)alkyl and        fluoro-(C₁₋₃)alkyl;        (76) each of R₁₁ and R₁₂ is independently selected from the        group, consisting of hydrogen, methyl, fluoromethyl,        difluoromethyl and trifluoromethyl;        (77) R₁₁ and R₁₂ is hydrogen;        (78) R₁₁ and R₁₂, taken together, are oxo;        (79) either        each of R₁₃ and R₁₄ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;        or        R₁₃ and R₁₄, taken together, are oxo or —CH₂—CH₂—;        (80) each of R₁₃ and R₁₄ is hydrogen.

The skilled person would understand that the embodiments (1) to (80) maybe used independently, collectively or in any combination orsub-combination to the limit the scope of the invention as describedhereinbefore in relation to compounds of the formula I, la, Ib, Ic, Idor Ie.

In one embodiment, the invention relates to a compound of the formula

in which

-   -   X₁ is CR₁ or N;    -   X₃ is CR₃ or N;    -   X₄ is CR₄ or N;    -   wherein at least one of X₁, X₃ and X₄ is N and not more than 2        of X₁, X₃ and X₄ are N;    -   R₁ is hydrogen, cyano, halogen, (C₁₋₄)alkyl,        halogen-(C₁₋₄)alkyl, (C₁₋₄)alkoxy, or halogen-(C₁₋₄)alkoxy;    -   R₂ is a 5- or 6-membered heteroaryl group in which structure 1,        2, 3, or 4 ring members are hetero ring members independently        selected from the group consisting of a nitrogen ring member, an        oxygen ring member and a sulfur ring member, which group is        optionally substituted by 1, 2, 3 or 4 substituents        independently selected from the group, consisting of cyano,        amino, aminocarbonyl, thiocarbamoyl, halogen, (C₁₋₄)alkyl,        halogen-(C₁₋₄)alkyl, hydroxy, oxo, (C₁₋₄)alkoxy,        halogen-(C₁₋₄)alkoxy, (C₁₋₄)alkylthio, halogen-(C₁₋₄)alkylthio,        (C₁₋₄)alkoxy-(C₁₋₄ alkyl, (C₁₋₄ alkoxy-(C₁₋₄ alkoxy,        (C₁₋₄)alkoxy-(C₁₋₄ alkylthio, (C₁₋₄ alkylthio-(C₁₋₄)alkyl, (C₁₋₄        alkylthio-(C₁₋₄)alkoxy, (C₁₋₄ alkylthio-(C₁₋₄)alkylthio,        (C₂₋₄)alkenyl, (C₂₋₄)alkynyl, (C₂₋₄)alkenoxy, and        (C₂₋₄)alkynoxy;    -   R₃, R₄ and R₅ are independently selected from the group        consisting of hydrogen, cyano, halogen, (C₁₋₄ alkyl,        halogen-(C₁₋₄ alkyl, (C₁₋₄ alkoxy, or halogen-(C₁₋₄ alkoxy;    -   R₆ is (C₁₋₃)alkyl or fluoro-(C₁₋₃)alkyl; and    -   each of R₁₁ and R₁₂ is independently selected from the group,        consisting of hydrogen, (C₁₋₃)alkyl and halogen-(C₁₋₃)alkyl;        or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention relates to a compound of theformula Ic

-   -   in which    -   X₁ is CH or N;    -   X₃ is CH or N;    -   X₄ is CR₄ or N;    -   wherein one and not more than one of X₁, X₃ and X₄ is N;    -   R₂ is a pyridyl or pyrazinyl group which is optionally        substituted by 1, 2 or 3 substituents independently selected        from the group, consisting of cyano, amino, aminocarbonyl,        thiocarbamoyl, halogen, (C₁₋₄)alkyl, halogen-(C₁₋₄)alkyl,        hydroxy, oxo, (C₁₋₄)alkoxy, halogen-(C₁₋₄)alkoxy, (C₁₋₄        alkylthio, halogen-(C₁₋₄)alkylthio, (C₁₋₄ alkoxy-(C₁₋₄ alkyl,        (C₁₋₄)alkoxy-(C₁₋₄)alkoxy, (C₁₋₄)alkoxy-(C₁₋₄)alkylthio,        (C₁₋₄)alkylthio-(C₁₋₄)alkyl, (C₁₋₄)alkylthio-(C₁₋₄)alkoxy,        (C₁₋₄)alkylthio-(C₁₋₄)alkylthio, (C₂₋₄)alkenyl, (C₂₋₄)alkynyl,        (C₂₋₄)alkenoxy, and (C₂₋₄)alkynoxy;    -   R₄ and R₅ are independently hydrogen, or halogen;    -   R₆ is (C₁₋₃)alkyl or fluoro-(C₁₋₃)alkyl; and    -   each of R₁₁ and R₁₂ is independently selected from the group,        consisting of hydrogen, (C₁₋₃)alkyl and fluoro-(C₁₋₃)alkyl;        or a pharmaceutically acceptable salt thereof.

In a further embodiment, the invention relates to a compound of theformula

in which

-   -   X₁ is CH or N;    -   X₃ is CH or N;    -   X₄ is CR₄ or N;    -   wherein one and not more than one of X₁, X₃ and X₄ is N;    -   R₂ is a pyridyl or pyrazinyl group which is substituted by 2 or        3 substituents and wherein one of the substituents is located at        the para position and one of the substituents is located at the        ortho position of the pyridyl or pyrazinyl group relative to the        amide linker and wherein the substituents are independently        selected from the group, consisting of cyano, amino, halogen,        (C₁₋₄)alkyl, halogen-(C₁₋₄)alkyl, hydroxy, oxo, (C₁₋₄)alkoxy and        halogen-(C₁₋₄)alkoxy;    -   R₄ and R₅ are independently hydrogen, or halogen;    -   R₆ is methyl, fluoromethyl, difluoromethyl or trifluoromethyl;        and    -   each of R₁₁ and R₁₂ is independently selected from the group,        consisting of hydrogen, methyl, fluoromethyl, difluoromethyl and        trifluoromethyl;        or a pharmaceutically acceptable salt thereof.

In a further embodiment, the invention relates to a compound of theformula

in which

-   -   R₂ is a pyridin-2-yl or pyrazin-2-yl group which is substituted        by 2 substituents and wherein one of the substituents is located        at the para position and one of the substituents is located at        the ortho position of the pyridin-2-yl or pyrazin-2-yl group        relative to the amide linker and wherein the substituents are        independently selected from the group, consisting of cyano,        amino, fluoro, bromo, chloro, hydroxyl, oxo, methyl,        fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,        fluoromethoxy, difluoromethoxy and trifluromethoxy;    -   R₅ is hydrogen or fluoro;    -   R₆ is methyl, fluoromethyl or difluoromethyl; and    -   each of R₁₁ and R₁₂ is independently selected from the group,        consisting of hydrogen, methyl, fluoromethyl, difluoromethyl and        trifluoromethyl;        or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention relates to a compound of theinvention which is selected from:

-   5-Bromo-pyridine-2-carboxylic acid    [6-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]-oxazin-3-yl)-pyridin-2-yl]-amide;-   5-Chloro-pyridine-2-carboxylic acid    [6-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [6-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   5-Cyano-3-methyl-pyridine-2-carboxylic acid    [6-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   4,6-Dideutero-5-chloro-3-trideuteromethyl-pyridine-2-carboxylic acid    [6-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   5-Thiocarbamoyl-pyridine-2-carboxylic acid    [6-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   5-Cyano-3-methyl-pyridine-2-carboxylic acid    [6-(5-amino-3,6-dimethyl-6-trifluoro-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   5-Cyano-pyridine-2-carboxylic acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   5-Cyano-3-methyl-pyridine-2-carboxylic acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;-   4,6-Dideutero-5-chloro-3-trideuteromethyl-pyridine-2-carboxylic acid    [4-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   5-Chloro-pyridine-2-carboxylic acid    [4-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   5-Cyano-3-methyl-pyridine-2-carboxylic acid    [4-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [5-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-6-chloro-pyridin-3-yl]-amide;-   3-Amino-5-cyano-pyridine-2-carboxylic acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   3-Chloro-5-cyano-pyridine-2-carboxylic acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]amide;-   5-Chloro-4,6-dideuterio-3-trideuteriomethyl-pyridine-2-carboxylic    acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   5-Bromo-3-chloro-pyridine-2-carboxylic acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   3-Amino-5-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   3-Chloro-5-cyano-pyridine-2-carboxylic acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;-   5-Methoxy-3-methyl-pyridine-2-carboxylic acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   3-Amino-5-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   3-Amino-5-cyano-pyridine-2-carboxylic acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   5-Difluoromethoxy-3-methyl-pyridine-2-carboxylic acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   3-Chloro-5-difluoromethoxy-pyridine-2-carboxylic acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   3,5-Dichloro-pyridine-2-carboxylic acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   5-Fluoromethoxy-3-methyl-pyridine-2-carboxylic acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   5-Methyl-pyrazine-2-carboxylic acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   3-Chloro-5-cyano-pyridine-2-carboxylic acid    [4-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;-   3-Chloro-5-difluoromethoxy-pyridine-2-carboxylic acid    [4-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;-   5-Cyano-3-methyl-pyridine-2-carboxylic acid    [4-(5-amino-6,6-bis-fluoromethyl-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;-   5-Cyano-3-methyl-pyridine-2-carboxylic acid    [6-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]    oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;-   3-Chloro-5-cyano-pyridine-2-carboxylic acid    [6-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]    oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;-   3,5-Dimethyl-pyrazine-2-carboxylic acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   3-Amino-5-(3-fluoro-propoxy)-pyrazine-2-carboxylic acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   3-Amino-5-(2-methoxy-ethyl)-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic    acid    [6-((5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   3-Amino-5-trifluoromethyl-pyrazine-2-carboxylic acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   3-Amino-5-(2,2-difluoro-ethyl)-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic    acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;-   4-Chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;-   6-Chloro-1-(2,2-difluoro-ethyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylic    acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;    and-   6-Chloro-1-(2-methoxy-ethyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylic    acid    [6-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;    and pharmaceutically acceptable salts thereof.

In another embodiment, the invention relates to a compound of theinvention which is selected from:

-   5-Bromo-pyridine-2-carboxylic acid    [6-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]-oxazin-3-yl)-pyridin-2-yl]-amide;-   5-Chloro-pyridine-2-carboxylic acid    [6-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [6-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   5-Cyano-3-methyl-pyridine-2-carboxylic acid    [6-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   4,6-Dideutero-5-chloro-3-trideuteromethyl-pyridine-2-carboxylic acid    [6-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   5-Thiocarbamoyl-pyridine-2-carboxylic acid    [6-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]amide;-   5-Cyano-3-methyl-pyridine-2-carboxylic acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoro-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   5-Cyano-pyridine-2-carboxylic acid    [6-((3S,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   5-Cyano-pyridine-2-carboxylic acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   5-Cyano-3-methyl-pyridine-2-carboxylic acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoro-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;-   5-Cyano-3-methyl-pyridine-2-carboxylic acid    [6-((3S,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;-   4,6-Dideutero-5-chloro-3-trideuteromethyl-pyridine-2-carboxylic acid    [4-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   5-Chloro-pyridine-2-carboxylic acid    [4-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   5-Cyano-3-methyl-pyridine-2-carboxylic acid    [4-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;-   5-Cyano-3-methyl-pyridine-2-carboxylic acid    [4-((3S,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [5-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-6-chloro-pyridin-3-yl]-amide;-   3-Amino-5-cyano-pyridine-2-carboxylic acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   3-Chloro-5-cyano-pyridine-2-carboxylic acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   5-Chloro-4,6-dideuterio-3-trideuteriomethyl-pyridine-2-carboxylic    acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   5-Bromo-3-chloro-pyridine-2-carboxylic acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   3-Amino-5-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide;-   3-Chloro-5-cyano-pyridine-2-carboxylic acid [6-((3R,    6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;-   5-Methoxy-3-methyl-pyridine-2-carboxylic acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   3-Amino-5-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   3-Amino-5-cyano-pyridine-2-carboxylic acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   3-Chloro-5-cyano-pyridine-2-carboxylic acid    [6-((3S,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   5-Difluoromethoxy-3-methyl-pyridine-2-carboxylic acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   3-Chloro-5-difluoromethoxy-pyridine-2-carboxylic acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   3,5-Dichloro-pyridine-2-carboxylic acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   5-Fluoromethoxy-3-methyl-pyridine-2-carboxylic acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   5-Methyl-pyrazine-2-carboxylic acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   3-Chloro-5-cyano-pyridine-2-carboxylic acid    [4-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;-   3-Chloro-5-difluoromethoxy-pyridine-2-carboxylic acid    [4-((3S,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;-   5-Cyano-3-methyl-pyridine-2-carboxylic acid    [4-((R)-5-amino-6,6-bis-fluoromethyl-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   5-Cyano-3-methyl-pyridine-2-carboxylic acid    [6-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]    oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;-   5-Cyano-3-methyl-pyridine-2-carboxylic acid    [6-((S)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]    oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;-   3-Chloro-5-cyano-pyridine-2-carboxylic acid    [6-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]    oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;-   3,5-Dimethyl-pyrazine-2-carboxylic acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   3-Amino-5-(3-fluoro-propoxy)-pyrazine-2-carboxylic acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   3-Amino-5-(2-methoxy-ethyl)-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic    acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   3-Amino-5-trifluoromethyl-pyrazine-2-carboxylic acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide;-   3-Amino-5-(2,2-difluoro-ethyl)-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic    acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;-   4-Chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;-   6-Chloro-1-(2,2-difluoro-ethyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylic    acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;    and-   6-Chloro-1-(2-methoxy-ethyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylic    acid    [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide;    and pharmaceutically acceptable salts thereof.

In a further aspect, the invention relates to a process for thepreparation of a compound of the formula I, in free form or in saltform, comprising

a) the reaction of a compound of the formula

in free form or in salt form, in which X₁, X₃, X₄, X₅, R₆, E₁ and E₂ areas defined for the formula I and PG is a protecting group, with acompound of the formula

in which R₂ is as defined for the formula I and L is a leaving group,for example a hydroxy group, in free form or in salt form,b) the reaction of a compound of the formula

in free form or in salt form, in which X₁, X₃, X₄, X₅, R₆, E₁ and E₂ areas defined for the formula I, Hal is halogen, for example bromine, andPG is a protecting group, with a compound of the formula

in which R₂ is as defined for the formula I, in free form or in saltform,c) the reaction of a compound of the formula

in which X₁, X₃, X₄, X₅, R₂, R₆, E₁ and E₂ are as defined for theformula I, in free form or in salt form, with ammonia,d) the optional reduction, oxidation or other functionalisation of theresulting compound,e) the cleavage of any protecting group(s) optionally present andf) the recovery of the so obtainable compound of the formula I in freeform or in salt form.

The reactions can be effected according to conventional methods, forexample as described in the Examples.

The working-up of the reaction mixtures and the purification of thecompounds thus obtainable may be carried out in accordance with knownprocedures.

Salts may be prepared from free compounds in known manner, andvice-versa.

In more detail, the reaction of a compound of formula (II) with acompound of formula (III) as described in step a) may be carried out inthe presence of a suitable coupling agent, for example1-hydroxy-7-azabenzotriazole, a suitable activating agent, for example1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, a suitablebase, for example diisopropylethylamine, a suitable solvent, for exampledimethylformamide, and at a suitable temperature, for example 0 to 50°C., more suitably 0 to 25° C.

In more detail, the reaction of a compound of formula (IIa) with acompound of formula (IIIa) as described in step b) may be carried out inthe presence of, a suitable catalyst, for exampletris(dibenzylidene-acetone) di palladium, a suitable ligand, for exampleXanthphos, a suitable base, for example cesium carbonate, a suitablesolvent, for example 1,4-dioxane, and at a suitable temperature, forexample 10 to 100° C., more suitably 30 to 85° C.

In more detail, the reaction of a compound of formula (IV) with ammoniaas described in step c) may be carried out in the presence of a suitablesolvent, for example methanol, and at a suitable temperature, forexample 0 to 50° C., more suitably 0 to 30° C.

Compounds of the formula I can also be prepared by further processes,which processes are further aspects of the invention, for example asdescribed in the Examples.

The starting materials of the formulae II, IIa, III, IIIa and IV areknown or may be prepared according to conventional procedures startingfrom known compounds, may be prepared from known compounds as describedin the Examples or may be prepared using procedures analogous to thosedescribed in the Examples.

Compounds of the formula I, in free form, salt form, or inpharmaceutically acceptable salt form, hereinafter often referred to as“agents of the invention”, exhibit valuable pharmacological properties,when tested in vitro or in vivo, and may, therefore, be useful inmedicaments, in therapy or for use as research chemicals, for example astool compounds.

For example, agents of the invention are inhibitors of BACE-1 and BACE-2and may be used for the treatment or prevention of a condition, diseaseor disorder involving processing by such enzymes, particularly thegeneration of beta-amyloid and the subsequent aggregation into oligomersand fibrils, and loss of β cell mass and/or function.

The inhibiting properties of an agent of the invention towards proteasescan be evaluated in tests as described hereinafter.

Test 1: Inhibition of Human BACE-1

Recombinant BACE-1 (extracellular domain, expressed in baculovirus andpurified using standard methods) at 0.1 to 10 nM concentrations isincubated with the test compound at various concentrations for 1 hour atroom temperature in 10 to 100 mM acetate buffer, pH 4.5, containing 0.1%CHAPS. Synthetic fluorescence-quenched peptide substrate, derived fromthe sequence of APP and containing a suitable fluorophore-quencher pair,is added to a final concentration of 1 to 5 μM, and the increase influorescence is recorded at a suitable excitation/emission wavelength ina microplate spectro-fluorimeter for 5 to 30 minutes in 1-minuteintervals. IC₅₀ values are calculated from percentage of inhibition ofBACE-1 activity as a function of the test compound concentration.

Test 2: Inhibition of Human BACE-2

Recombinant BACE-2 (extracellular domain, expressed in baculovirus andpurified using standard methods) at 0.1 to 10 nM concentrations isincubated with the test compound at various concentrations for 1 hour atroom temperature in 10 to 100 mM acetate buffer, pH 4.5, containing 0.1%CHAPS. Synthetic fluorescence-quenched peptide substrate, derived fromthe sequence of APP and containing a suitable fluorophore-quencher pair,is added to a final concentration of 1 to 5 μM, and the increase influorescence is recorded at a suitable excitation/emission wavelength ina microplate spectro-fluorimeter for 5 to 30 minutes in 1-minuteintervals. IC₅₀ values are calculated from percentage of inhibition ofBACE-2 activity as a function of the test compound concentration.

Test 3: Inhibition of Human Cathepsin D

Recombinant cathepsin D (expressed as procathepsin D in baculovirus,purified using standard methods and activated by incubation in sodiumformate buffer pH 3.7) is incubated with the test compound at variousconcentrations for 1 hour at room temperature in sodium formate orsodium acetate buffer at a suitable pH within the range of pH 3.0 to5.0. Synthetic peptide substrateMca-Gly-Lys-Pro-Ile-Leu-Phe-Phe-Arg-Leu-Lys(DNP)-D-Arg-N H₂ is added toa final concentration of 1 to 5 μM, and the increase in fluorescence isrecorded at excitation of 325 nm and emission at 400 nm in a microplatespectro-fluorimeter for 5 to 30 minutes in 1-minute intervals. IC₅₀values are calculated from the percentage of inhibition of cathepsinD-activity as a function of the test compound concentration.

Test 4: Inhibition of Cellular Release of Amyloid Peptide 1-40

Chinese hamster ovary cells are transfected with the human gene foramyloid precursor protein. The cells are plated at a density of 8000cells/well into 96-well microtiter plates and cultivated for 24 hours inDMEM cell culture medium containing 10% FCS. The test compound is addedto the cells at various concentrations, and the cells are cultivated for24 hours in the presence of the test compound. The supernatants arecollected, and the concentration of amyloid peptide 1-40 is determinedusing state of the art immunoassay techniques, for example sandwichELISA, homogenous time-resolved fluorescence (HTRF) immunoassay, orelectro-chemiluminescence immunoassay. The potency of the compound iscalculated from the percentage of inhibition of amyloid peptide releaseas a function of the test compound concentration.

Agents of the invention were tested in at least one of theabove-described tests.

The compounds of the Examples show the following mean IC₅₀ values inTest 1 described hereinbefore:

TABLE 1 Example BACE-1 IC₅₀ [μM] Example BACE-1 IC₅₀ [μM] 1 0.39 2 0.793 2.6 4 1.6 5 0.27 6 0.55 7 2.1 8 0.005 9 6.2 10 0.039 11 0.004 12 0.4913 3.7 14 8.1 15 >10 16 0.082 17 7.6 18 0.14 19 0.043 20 0.01 21 0.03122 0.013 23 1.2 24 0.006 25 0.093 26 0.4 27 0.011 28 1.1 29 0.026 300.025 31 0.007 32 0.045 33 0.82 34 0.007 35 0.15 36 0.41 37 0.38 380.033 39 1.5 40 0.042 41 0.23 42 0.2 43 1.2 44 0.04 45 >10 46 0.0147 >10 48 7.3

The compounds of the Examples show the following mean IC₅₀ values inTest 2 described hereinbefore:

TABLE 2 Example BACE-2 IC₅₀ [μM] Example BACE-2 IC₅₀ [μM] 1 0.26 2 0.363 1.4 4 1.7 5 1 6 0.24 7 8.7 8 0.02 9 9.9 10 0.1 11 0.012 12 1.3 13 1.514 4.8 15 >10 16 0.055 17 4.2 18 0.13 19 0.082 20 0.041 21 0.008 220.005 23 >10 24 0.01 25 0.015 26 6.4 27 0.012 28 1.9 29 0.024 30 0.02431 0.001 32 0.007 33 0.33 34 0.03 35 0.12 36 0.28 37 0.43 38 0.16 39 6.540 0.17 41 0.13 42 1.0 43 >10 44 0.18 45 >10 46 0.005 47 5.4 48 >10

Compounds of the Examples show the following mean IC₅₀ values in Test 4described hereinbefore:

TABLE 3 Amyloid-β1-40 Amyloid-β1-40 Example release IC₅₀ [μM] Examplerelease IC₅₀ [μM] 1 0.041 2 0.058 3 0.14 4 0.098 5 0.04 6 0.063 7 0.64 80.006 9 1.9 10 0.017 11 0.002 12 0.28 13 0.55 14 0.66 15 NT 16 0.077 174.8 18 0.015 19 0.048 20 0.005 21 0.11 22 0.029 23 0.7 24 0.003 25 0.07626 0.28 27 0.005 28 NT 29 0.024 30 0.024 31 0.01 32 0.026 33 0.13 340.003 35 0.14 36 0.41 37 0.083 38 0.005 39 0.29 40 0.012 41 0.161 420.072 43 0.37 44 0.03 45 3.6 46 NT 47 NT 48 NT NT = Not Tested

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drugs, drug stabilizers, binders, excipients,disintegration agents, lubricants, sweetening agents, flavoring agents,dyes, and the like and combinations thereof, as would be known to thoseskilled in the art (see, for example, Remington's PharmaceuticalSciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Exceptinsofar as any conventional carrier is incompatible with the activeingredient, its use in the therapeutic or pharmaceutical compositions iscontemplated.

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response of asubject, for example, reduction or inhibition of an enzyme or a proteinactivity, or ameliorate symptoms, alleviate conditions, slow or delaydisease progression, or prevent a disease, etc. In one non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a subject, is effective to (1) at least partially alleviating,inhibiting, preventing and/or ameliorating a condition, or a disorder ora disease (i) mediated by BACE-1 or (ii) associated with BACE-1activity, or (iii) characterized by activity (normal or abnormal) ofBACE-1; or (2) reducing or inhibiting the activity of BACE-1. In anothernon-limiting embodiment, the term “a therapeutically effective amount”refers to the amount of the compound of the present invention that, whenadministered to a cell, or a tissue, or a non-cellular biologicalmaterial, or a medium, is effective to at least partially reduce orinhibit the activity of BACE-1. The meaning of the term “atherapeutically effective amount” as illustrated in the aboveembodiments for BACE-1 also applies by the same means to any otherrelevant proteins/peptides/enzymes, such as BACE-2, or cathepsin D.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A subject also refers to for example, primates(e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats,rabbits, rats, mice, fish, birds and the like. In certain embodiments,the subject is a primate. In yet other embodiments, the subject is ahuman.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In yet another embodiment, “treat”, “treating” or “treatment”refers to modulating the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both.

As used herein, the term “prevention” of any particular disease ordisorder refers to the administration of a compound of the invention toa subject before any symptoms of that disease or disorder are apparent.

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

As used herein, the term an “agent” of the invention is usedinterchangeably with the term a “compound” of the invention and has nodifference in meaning therefrom.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context. Theuse of any and all examples, or exemplary language (e.g. “such as”)provided herein is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention otherwiseclaimed.

Due to their inhibiting properties towards proteases, and BACE-1 inparticular, agents of the invention may be useful, e. g., in thetreatment or prevention of a variety of disabilitating psychiatric,psychotic, neurological or vascular states, e. g. of a condition,disease or disorder of the vascular system or of the nervous system, inwhich beta-amyloid generation or aggregation plays a role. Based on theinhibition of BACE-2 (beta-site APP-cleaving enzyme 2) or cathepsin D,which are close homologues of the pepsin-type aspartyl proteases andbeta-secretase, and the correlation of BACE-2 or cathepsin D expressionwith a more tumorigenic or metastatic potential of tumor cells, theagents of the invention may also be useful as anti-cancer medicaments,e. g. in the suppression of the metastasis process associated with tumorcells. Furthermore, based on the inhibition of BACE-2 and thecorrelation of BACE-2 activity with TME27 cleavage and β cell mass, theagents of the invention may also be useful for treating or preventingloss of β cell mass and/or function, e.g. in the treatment of diabetes.

The said condition, disease or disorder of the vascular system or of thenervous system is exemplified by, and includes, without limitation, ananxiety disorder, such as panic disorder with or without agoraphobia,agoraphobia without history of panic disorder, an animal or otherspecific phobia, including a social phobia, social anxiety disorder,anxiety, obsessive-compulsive disorder, a stress disorder, includingpost-traumatic or acute stress disorder, or a generalized orsubstance-induced anxiety disorder; a neurosis; seizures; epilepsy,especially partial seizures, simple, complex or partial seizuresevolving to secondarily generalized seizures or generalized seizures[absence (typical or atypical), myoclonic, clonic, tonic, tonic-clonicor atonic seizures]; convulsions; migraine; an affective disorder,including a depressive or bipolar disorder, e. g. single-episode orrecurrent major depressive disorder, major depression, a dysthymicdisorder, dysthymia, depressive disorder NOS, bipolar I or bipolar IImanic disorder or cyclothymic disorder; a psychotic disorder, includingschizophrenia or depression; neurodegeneration, e. g. neurodegenerationarising from cerebral ischemia; an acute, traumatic or chronicdegenerative process of the nervous system, such as Parkinson's disease,Down's syndrome, dementia, e. g. senile dementia, dementia with Lewybodies or a fronto-temporal dementia, a cognitive disorder, cognitiveimpairment, e. g. mild cognitive impairment, memory impairment, anamyloid neuropathy, a peripheral neuropathy, Alzheimer's disease,Gerstmann-Straeussler-Scheinker syndrome, Niemann-Pick disease, e. g.Niemann-Pick type C disease, brain inflammation, a brain, spinal cord ornerve injury, e. g. traumatic brain injury (TBI), a nerve trauma or abrain trauma, vascular amyloidosis, cerebral haemorrhage withamyloidosis, Huntington's chorea, amyotrophic lateral sclerosis,multiple sclerosis or fragile X syndrome; scrapie; cerebral amyloidangiopathy; an encephalopathy, e. g. transmissible spongiformencephalopathy; stroke; an attention disorder, e. g. attention deficithyperactivity disorder; Tourette's syndrome; a speech disorder,including stuttering; a disorder of the circadian rhythm, e. g. insubjects suffering from the effects of jet lag or shift work; pain;nociception; itch; emesis, including acute, delayed or anticipatoryemesis, such as emesis induced by chemotherapy or radiation, motionsickness, or post-operative nausea or vomiting; an eating disorder,including anorexia nervosa or bulimia nervosa; premenstrual syndrome; amuscle spasm or spasticity, e. g. in paraplegic patients; a hearingdisorder, e. g. tinnitus or age-related hearing impairment; urinaryincontinence; glaucoma; inclusion-body myositis; or a substance-relateddisorder, including substance abuse or dependency, including asubstance, such as alcohol, withdrawal disorder. Agents of the inventionmay also be useful in enhancing cognition, e. g. in a subject sufferingfrom a dementing condition, such as Alzheimer's disease; aspre-medication prior to anaesthesia or a minor medical intervention,such as endoscopy, including gastric endoscopy; or as ligands, e. g.radioligands or positron emission tomography (PET) ligands.

Due to their inhibiting properties towards BACE-2, compounds of theinvention may be useful in the treatment or prevention a disease ordisorder mediated by BACE-2. Diseases and disorders associated withBACE-2 include: metabolic syndrome (such as dyslipidemia, obesity,insulin resistance, hypertension, microalbuminemia, hyperuricaemia, andhypercoagulability), insulin resistance, glucose intolerance (also knownas impaired glucose tolerance or impaired glucose tolerance, IGT),obesity, hypertension, or diabetic complications (such as retinopathy,nephropathy, diabetic foot, ulcers, macroangiopathies, metabolicacidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia), glucosemetabolic disorder, dyslipidaemias of different origins, atherosclerosisand related diseases, high blood pressure, chronic heart failure,Syndrome X, diabetes, non-insulin-dependent diabetes mellitus, Type 2diabetes, Type 1 diabetes, body weight disorders, weight loss, body massindex and leptin related diseases.

Compounds of the invention may be suitable for preventing beta-celldegeneration such as apoptosis or necrosis of pancreatic beta cells, forimproving or restoring the functionality of pancreatic cells, and/orincreasing the number and/or size of pancreatic beta cells.

As used herein a patient is suffering from “obesity” if the patientexhibits at least one of:

-   -   a body mass index (BMI), i.e. the patient's mass (in kg) divided        by the square of the patient's height (in m), of 30 or more;    -   an absolute waist circumference of >102 cm in men or >88 cm in        women;    -   a waist-to-hip ratio >0.9 in men or >0.85 in women; or    -   a percent body fat >25% in men or >30% in women.

As used herein a patient is suffering from “Type 2 diabetes” if theymeet the World Health Organisation criteria for Diabetes diagnosis(Definition and diagnosis of diabetes mellitus and intermediatehyperglycaemia, WHO, 2006), i.e. the patient exhibits at least one of:

-   -   a fasting plasma glucose ≥7.0 mmol/l (126 mg/dl); or    -   a venous plasma glucose ≥11.1 mmol/l (200 mg/dl) 2 hours after        ingestion of 75 g oral glucose load.

As used herein a patient is suffering from “IGT” if they meet the WorldHealth Organisation criteria for IGT diagnosis (Definition and diagnosisof diabetes mellitus and intermediate hyperglycaemia, WHO, 2006), i.e.the patient exhibits both of:

-   -   a fasting plasma glucose <7.0 mmol/l (126 mg/dl); and    -   a venous plasma glucose ≥7.8 and <11.1 mmol/l (200 mg/dl) 2        hours after ingestion of 75 g oral glucose load.

As used herein, the term “metabolic syndrome” is a recognized clinicalterm used to describe a condition comprising combinations of Type IIdiabetes, impaired glucose tolerance, insulin resistance, hypertension,obesity, increased abdominal girth, hypertriglyceridemia, low HDL,hyperuricaernia, hypercoagulability and/or microalbuminemia. TheAmerican Heart Association has published guidelines for the diagnosis ofmetabolic syndrome, Grundy, S., et. al., (2006) Cardiol. Rev. Vol. 13,No. 6, pp. 322-327.

For the above-mentioned indications, the appropriate dosage will varydepending on, e. g., the compound employed as active pharmaceuticalingredient, the host, the mode of administration, the nature andseverity of the condition, disease or disorder or the effect desired.

However, in general, satisfactory results in animals are indicated to beobtained at a daily dosage of from about 0.1 to about 100, preferablyfrom about 1 to about 50, mg/kg of animal body weight. In largermammals, for example humans, an indicated daily dosage is in the rangeof from about 0.5 to about 2000, preferably from about 2 to about 200,mg of an agent of the invention conveniently administered, for example,in divided doses up to four times a day or in sustained release form.

An agent of the invention may be administered by any conventional route,in particular enterally, preferably orally, e. g. in the form of atablet or capsule, or parenterally, e. g. in the form of an injectablesolution or suspension.

In a further aspect, the invention relates to a pharmaceuticalcomposition comprising an agent of the invention as activepharmaceutical ingredient in association with at least onepharmaceutically acceptable carrier or diluent and optionally inassociation with other auxiliary substances, such as inhibitors ofcytochrome P450 enzymes, agents preventing the degradation of activepharmaceutical ingredients by cytochrome P450, agents improving orenhancing the pharmacokinetics of active pharmaceutical ingredients,agents improving or enhancing the bioavailability of activepharmaceutical ingredients, and so on, e. g. grapefruit juice,ketoconazole or, preferably, ritonavir. Such a composition may bemanufactured in conventional manner, e. g. by mixing its components.Unit dosage forms contain, e. g., from about 0.1 to about 1000,preferably from about 1 to about 500, mg of an agent of the invention.

In addition, the pharmaceutical compositions of the present inventioncan be made up in a solid form (including without limitation capsules,tablets, pills, granules, powders or suppositories), or in a liquid form(including without limitation solutions, suspensions or emulsions). Thepharmaceutical compositions can be subjected to conventionalpharmaceutical operations such as sterilization and/or can containconventional inert diluents, lubricating agents, or buffering agents, aswell as adjuvants, such as preservatives, stabilizers, wetting agents,emulsifiers and buffers, etc.

Typically, the pharmaceutical compositions are tablets or gelatincapsules comprising the active ingredient together with

-   -   a) diluents, e.g., lactose, dextrose, sucrose, mannitol,        sorbitol, cellulose and/or glycine;    -   b) lubricants, e.g., silica, talcum, stearic acid, its magnesium        or calcium salt and/or polyethyleneglycol; for tablets also    -   c) binders, e.g., magnesium aluminum silicate, starch paste,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and/or polyvinylpyrrolidone; if desired    -   d) disintegrants, e.g., starches, agar, alginic acid or its        sodium salt, or effervescent mixtures; and/or    -   e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets may contain the active ingredient in admixturewith nontoxic pharmaceutically acceptable excipients which are suitablefor the manufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, or contain about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with a suitable carrier. Carrierssuitable for transdermal delivery include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Forexample, transdermal devices are in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundof the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. They arethus particularly suited for use in topical, including cosmetic,formulations well-known in the art. Such may contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

As used herein a topical application may also pertain to an inhalationor to an intranasal application. They may be conveniently delivered inthe form of a dry powder (either alone, as a mixture, for example a dryblend with lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurised container, pump, spray, atomizer ornebuliser, with or without the use of a suitable propellant.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compounds of the presentinvention as active ingredients, since water may facilitate thedegradation of certain compounds.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. An anhydrous pharmaceuticalcomposition may be prepared and stored such that its anhydrous nature ismaintained. Accordingly, anhydrous compositions are packaged usingmaterials known to prevent exposure to water such that they can beincluded in suitable formulary kits. Examples of suitable packaginginclude, but are not limited to, hermetically sealed foils, plastics,unit dose containers (e. g., vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

In accordance with the foregoing, in a further aspect, the inventionrelates to an agent of the invention for use as a medicament, forexample for the treatment or prevention of a neurological or vascularcondition, disease or disorder, in which beta-amyloid generation oraggregation plays a role, or for the suppression of the metastasisprocess associated with tumor cells, or for the treatment or preventionof loss of β cell mass and/or function. In one embodiment, the inventionrelates to an agent of the invention for use in the treatment of adisease or disorder mediated by BACE-1, BACE-2 or cathepsin D activity.In another embodiment, the invention relates to an agent of theinvention for use in the treatment or prevention of Alzheimer's Diseaseor mild cognitive impairment. In a further embodiment, the inventionrelates to an agent of the invention for use in the treatment orprevention of insulin resistance, glucose intolerance, type 2 diabetes,obesity, hypertension, or diabetic complications. In yet anotherembodiment, the invention relates to a compound of the invention for usein the treatment of impaired glucose tolerance or Type 2 diabetes.

In a further aspect, the invention relates to the use of an agent of theinvention as an active pharmaceutical ingredient in a medicament, forexample for the treatment or prevention of a neurological or vascularcondition, disease or disorder, in which beta-amyloid generation oraggregation plays a role, or for the suppression of the metastasisprocess associated with tumor cells, or for the treatment or preventionof loss of β cell mass and/or function. In a further embodiment, theinvention relates to the use of an agent of the invention as an activepharmaceutical ingredient in a medicament for the treatment orprevention of a disease or disorder mediated by BACE-1, BACE-2 orcathepsin D activity. In one embodiment, the invention relates to theuse of an agent of the invention as an active pharmaceutical ingredientin a medicament for the treatment or prevention of Alzheimer's Diseaseor mild cognitive impairment. In a further embodiment, the inventionrelates to the use of a compound of the invention as an activepharmaceutical ingredient in a medicament for the treatment orprevention of insulin resistance, glucose intolerance, type 2 diabetes,obesity, hypertension, or diabetic complications. In yet a furtherembodiment, the invention relates to the use of a compound of theinvention as an active pharmaceutical ingredient in a medicament for thetreatment or prevention of impaired glucose tolerance or Type 2diabetes.

In a further aspect, the invention relates to the use of an agent of theinvention for the manufacture of a medicament for the treatment orprevention of a neurological or vascular condition, disease or disorder,in which beta-amyloid generation or aggregation plays a role, or for thesuppression of the metastasis process associated with tumor cells, orfor the treatment or prevention of loss of β cell mass and/or function.In a further embodiment, the invention relates to the use of an agent ofthe invention for the manufacture of a medicament for the treatment orprevention of a disease or disorder mediated by BACE-1, BACE-2 orcathepsin D activity. In one embodiment, the invention relates to theuse of an agent of the invention for the manufacture of a medicament forthe treatment or prevention of Alzheimer's Disease or mild cognitiveimpairment. In a further embodiment, the invention relates to the use ofa compound of the invention as an active pharmaceutical ingredient in amedicament for the treatment or prevention of insulin resistance,glucose intolerance, type 2 diabetes, obesity, hypertension, or diabeticcomplications. In yet a further embodiment, the invention relates to theuse of a compound of the invention as an active pharmaceuticalingredient in a medicament for the treatment or prevention of impairedglucose tolerance or Type 2 diabetes.

In a further aspect, the invention relates to a method for the treatmentor prevention of a neurological or vascular condition, disease ordisorder, in which beta-amyloid generation or aggregation plays a role,or for the suppression of the metastasis process associated with tumorcells, or for the treatment or prevention of loss of β cell mass and/orfunction, in a subject in need of such treatment, prevention orsuppression, which method comprises administering to such subject aneffective amount of an agent of the invention. In one embodiment, theinvention relates to a method of modulating BACE-1, BACE-2 or cathepsinD activity in a subject, wherein the method comprises administering tothe subject a therapeutically effective amount of an agent of theinvention. In another embodiment, the invention relates to a method forthe treatment or prevention of a disease mediated by BACE-1, BACE-2 orcathepsin D activity, in a subject in need of such treatment orprevention, which method comprises administering to such subject aneffective amount of an agent of the invention. In yet anotherembodiment, the invention relates to a method for the treatment orprevention of Alzheimer's Disease or mild cognitive impairment, in asubject in need of such treatment or prevention, which method comprisesadministering to such subject an effective amount of an agent of theinvention. In a further embodiment, the invention relates to a methodfor the treatment or prevention of insulin resistance, glucoseintolerance, type 2 diabetes, obesity, hypertension, or diabeticcomplications, in a subject in need of such treatment or prevention,which method comprises administering to such subject a therapeuticallyeffective amount of a compound of the invention. In yet a furtherembodiment, the invention relates to a method for the treatment orprevention of impaired glucose tolerance or Type 2 diabetes, in asubject in need of such treatment or prevention, which method comprisesadministering to such subject a therapeutically effective amount of acompound of the invention.

An agent of the invention can be administered as sole activepharmaceutical ingredient or as a combination with at least one otheractive pharmaceutical ingredient effective, e. g., in the treatment orprevention of a neurological or vascular condition, disease or disorder,in which beta-amyloid generation or aggregation plays a role, or in thesuppression of the metastasis process associated with tumor cells, or inthe treatment or prevention of loss of β cell mass and/or function. Sucha pharmaceutical combination may be in the form of a unit dosage form,which unit dosage form comprises a predetermined quantity of each of theat least two active components in association with at least onepharmaceutically acceptable carrier or diluent. Alternatively, thepharmaceutical combination may be in the form of a package comprisingthe at least two active components separately, e. g. a pack ordispenser-device adapted for the concomitant or separate administrationof the at least two active components, in which these active componentsare separately arranged. In a further aspect, the invention relates tosuch pharmaceutical combinations.

In a further aspect, the invention therefore relates to a pharmaceuticalcombination comprising a therapeutically effective amount of an agent ofthe invention and a second drug substance, for simultaneous orsequential administration.

In one embodiment, the invention provides a product comprising an agentof the invention and at least one other therapeutic agent as a combinedpreparation for simultaneous, separate or sequential use in therapy. Inone embodiment, the therapy is the treatment of a disease or conditionmediated by BACE-1, BACE-2 or cathepsin D activity, such as Alzheimer'sDisease, mild cognitive impairment, impaired glucose tolerance or type 2diabetes.

In one embodiment, the invention provides a pharmaceutical compositioncomprising an agent of the invention and another therapeutic agent(s).Optionally, the pharmaceutical composition may comprise apharmaceutically acceptable excipient, as described above.

In one embodiment, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains anagent of the invention. In one embodiment, the kit comprises means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is a blisterpack, as typically used for the packaging of tablets, capsules and thelike. The kit of the invention may be used for administering differentdosage forms, for example, oral and parenteral, for administering theseparate compositions at different dosage intervals, or for titratingthe separate compositions against one another. To assist compliance, thekit of the invention typically comprises directions for administration.

In the combination therapies of the invention, the agent of theinvention and the other therapeutic agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompound of the invention and the other therapeutic may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g. in the case of a kit comprisingthe compound of the invention and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (iii) in the patient themselves, e.g.during sequential administration of the compound of the invention andthe other therapeutic agent. Accordingly, the invention provides anagent of the invention for use in the treatment of a disease orcondition mediated by BACE-1, BACE-2 or cathepsin D activity, such asAlzheimer's Disease, impaired glucose tolerance or type 2 diabetes,wherein the medicament is prepared for administration with anothertherapeutic agent. The invention also provides the use of anothertherapeutic agent for treating a disease or condition mediated byBACE-1, BACE-2 or cathepsin D activity, such as Alzheimer's Disease,impaired glucose tolerance or type 2 diabetes, wherein the medicament isadministered with an agent of the invention.

The invention also provides an agent of the invention for use in amethod of treating a disease or condition mediated by BACE-1, BACE-2 orcathepsin D activity, such as Alzheimer's Disease, impaired glucosetolerance or type 2 diabetes, wherein the agent of the invention isprepared for administration with another therapeutic agent. Theinvention also provides another therapeutic agent for use in a method oftreating a disease or condition mediated by BACE-1, BACE-2 or cathepsinD activity, such as Alzheimer's Disease, impaired glucose tolerance ortype 2 diabetes, wherein the other therapeutic agent is prepared foradministration with an agent of the invention. The invention alsoprovides an agent of the invention for use in a method of treating adisease or condition mediated by BACE-1, BACE-2 or cathepsin D activity,such as Alzheimer's Disease, impaired glucose tolerance or type 2diabetes, wherein the agent of the invention is administered withanother therapeutic agent. The invention also provides anothertherapeutic agent for use in a method of treating a disease or conditionmediated by BACE-1, BACE-2 or cathepsin D activity, such as Alzheimer'sDisease, impaired glucose tolerance or type 2 diabetes, wherein theother therapeutic agent is administered with an agent of the invention.

The invention also provides the use of an agent of the invention fortreating a disease or condition mediated by BACE-1, BACE-2 or cathepsinD activity, such as Alzheimer's Disease, impaired glucose tolerance ortype 2 diabetes, wherein the patient has previously (e.g. within 24hours) been treated with another therapeutic agent. The invention alsoprovides the use of another therapeutic agent for treating a disease orcondition mediated by BACE-1, BACE-2 or cathepsin D activity, such asAlzheimer's Disease, impaired glucose tolerance or type 2 diabetes,wherein the patient has previously (e.g. within 24 hours) been treatedwith an agent of the invention.

In one embodiment, the invention relates to a compound of the inventionin combination with another therapeutic agent wherein the othertherapeutic agent is selected from:

(a) acetylcholinesterase inhibitors, such as donepezil (Aricept™),rivastigmine (Exelon™) and galantamine (Razadyne™);

(b) glutamate antagonists, such as memantine (Namenda™);

(c) antidepressant medications for low mood and irritability, such ascitalopram (Celexa™) fluoxetine (Prozac™), paroxeine (Paxil™),sertraline (Zoloft™) and trazodone (Desyrel™);

(d) anxiolytics for anxiety, restlessness, verbally disruptive behaviorand resistance, such as lorazepam (Ativan™) and oxazepam (Serax™);

(e) antipsychotic medications for hallucinations, delusions, aggression,agitation, hostility and uncooperativeness, such as aripiprazole(Abilify™), clozapine (Clozaril™), haloperidol (Haldol™), olanzapine(Zyprexa™), quetiapine (Seroquel™), risperidone (Risperdal™) andziprasidone (Geodon™);(f) mood stabilizers, such as carbamazepine (Tegretol™) and divalproex(Depakote™);(g) nicotinic apha—7 agonists;(h) mGluR5 antagonists;(i) H3 agonists; and(j) amyloid therapy vaccines.

Thus, in one embodiment, the invention provides a pharmaceuticalcomposition comprising:

i) a compound of the invention, or a pharmaceutically acceptable saltthereof;

ii) at least one compound selected from:

-   -   a) acetylcholinesterase inhibitors,    -   b) glutamate antagonists,    -   c) antidepressant medications,    -   d) anxiolytics,    -   e) antipsychotic medications,    -   f) mood stabilizers,    -   g) nicotinic apha—7 agonists,    -   h) mGluR5 antagonists,    -   i) H3 agonists, and    -   j) amyloid therapy vaccines; and        ii) one or more pharmaceutically acceptable carriers.

In another embodiment, the invention relates to a compound of theinvention, or a pharmaceutically acceptable salt thereof, in combinationwith another therapeutic agent wherein the other therapeutic agent isselected from:

a) antidiabetic agents, such as insulin, insulin derivatives andmimetics; insulin secretagogues such as the sulfonylureas, e.g.,Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea receptorligands such as meglitinides, e.g., nateglinide and repaglinide; proteintyrosine phosphatase-1B (PTP-1B) inhibitors such as PTP-112; GSK3(glycogen synthase kinase-3) inhibitors such as SB-517955, SB-4195052,SB-216763, NN-57-05441 and NN-57-05445; RXR ligands such as GW-0791 andAGN-194204; sodium-dependent glucose cotransporter inhibitors such asT-1095; glycogen phosphorylase A inhibitors such as BAY R3401;biguanides such as metformin; alpha-glucosidase inhibitors such asacarbose; GLP-1 (glucagon like peptide-1), GLP-1 analogs such asExendin-4 and GLP-1 mimetics; and DPPIV (dipeptidyl peptidase IV)inhibitors such as vildagliptin;b) hypolipidemic agents such as 3-hydroxy-3-methyl-glutaryl coenzyme A(HMG-CoA) reductase inhibitors, e.g., lovastatin, pitavastatin,simvastatin, pravastatin, cerivastatin, mevastatin, velostatin,fluvastatin, dalvastatin, atorvastatin, rosuvastatin and rivastatin;squalene synthase inhibitors; FXR (farnesoid X receptor) and LXR (liverX receptor) ligands; cholestyramine; fibrates; nicotinic acid bile acidbinding resins such as cholestyramine; fibrates; nicotinic acid andother GPR109 agonists; cholesterol absorption inhibitors such asezetimibe; CETP inhibitors (cholesterol-ester-transfer-proteininhibitors), and aspirin;c) anti-obesity agents such as orlistat, sibutramine and CannabinoidReceptor 1 (CB1) antagonists e.g. rimonabant; andd) anti-hypertensive agents, e.g., loop diuretics such as ethacrynicacid, furosemide and torsemide; angiotensin converting enzyme (ACE)inhibitors such as benazepril, captopril, enalapril, fosinopril,lisinopril, moexipril, perinodopril, quinapril, ramipril andtrandolapril; inhibitors of the Na-K-ATPase membrane pump such asdigoxin; neutralendopeptidase (NEP) inhibitors; ACE/NEP inhibitors suchas omapatrilat, sampatrilat and fasidotril; angiotensin II antagonistssuch as candesartan, eprosartan, irbesartan, losartan, telmisartan andvalsartan, in particular valsartan; renin inhibitors such as ditekiren,zankiren, terlakiren, aliskiren, RO 66-1132 and RO-66-1168; β-adrenergicreceptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol,metoprolol, nadolol, propranolol, sotalol and timolol; inotropic agentssuch as digoxin, dobutamine and milrinone; calcium channel blockers suchas amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine,nifedipine, nisoldipine and verapamil; aldosterone receptor antagonists;and aldosterone synthase inhibitors.e) agonists of peroxisome proliferator-activator receptors, such asfenofibrate, pioglitazone, rosiglitazone, tesaglitazar, BMS-298585,L-796449, the compounds specifically described in the patent applicationWO 2004/103995 i.e. compounds of examples 1 to 35 or compoundsspecifically listed in claim 21, or the compounds specifically describedin the patent application WO 03/043985 i.e. compounds of examples 1 to 7or compounds specifically listed in claim 19 and especially(R)-1-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicor a salt thereof.

Thus, in one embodiment, the invention provides a pharmaceuticalcomposition comprising;

i) a compound of the invention, or a pharmaceutically acceptable saltthereof, and

ii) at least one compound selected from

-   -   a) antidiabetic agents,    -   b) hypolipidemic agents,    -   c) anti-obesity agents,    -   d) anti-hypertensive agents,    -   e) agonists of peroxisome proliferator-activator receptors, and        ii) one or more pharmaceutically acceptable carriers.

Other specific anti-diabetic compounds are described by Patel Mona inExpert Opin Investig Drugs, 2003, 12(4), 623-633, in the figures 1 to 7.

The structure of the therapeutic agents identified by code numbers,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g., PatentsInternational (e.g. IMS World Publications).

EXAMPLES

The following Examples illustrate the invention, but do not limit it.

Abbreviations

aq. aqueous

anhy. anhydrous

Boc tert-butoxycarbonyl

Boc₂O di-tert-butyl dicarbonate

t-Bu tert-butyl

t-BuOH tert-butanol

conc. concentrated

(1R)-(−)-10-CSA (1R)-(−)-10-Camphor sulphonic acid

DCM dichloromethane

DEA diethylamine

DIPEA diisopropylethylamine

DMAP 4-dimethyl amino pyridine

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

eq. equivalent(s)

ESI electrospray ionisation

ETA ethanol/conc. aq. ammonia 95/5

Et₃N triethylamine

Et₂O diethylether

EtOAc ethyl acetate

EtOH ethanol

h hour(s)

HOAt 1-hydroxy-7-azabenzotriazole

HPLC high performance liquid chromatography

LC liquid chromatography

MeOH methanol

min minute(s)

MS mass spectrometry

NEt₃ triethylamine

NMR nuclear magnetic resonance spectrometry

org organic

Rf retention factor

ROESY Rotating-frame Overhauser Effect SpectroscopY

Rt retention time (min)

rt room temperature

soln. solution

TBDMS tertiary butyl dimethyl silyl

TBME tert-butyl-methyl-ether

TFAA trifluoroacetic acid anhydride

THF tetrahydrofuran

TLC thin layer chromatography

UPLC ultra performance liquid chromatography

Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

NMR Methodology

Proton spectra are recorded on a Bruker 400 MHz ultrashield spectrometerunless otherwise noted. Chemical shifts are reported in ppm relative tomethanol (δ 3.31), dimethyl sulfoxide (δ 2.50), or chloroform (δ 7.29).A small amount of the dry sample (2-5 mg) is dissolved in an appropriatedeuterated solvent (0.7 mL). The shimming is automated and the spectraobtained in accordance with normal procedure.

General Chromatography Information

HPLC Method H1 (Rt_(H1)):

-   HPLC-column dimensions: 3.0×30 mm-   HPLC-column type: Zorbax SB-C18, 1.8 μm-   HPLC-eluent: A) water+0.05 Vol.-% TFA; B) ACN+0.05 Vol.-% TFA-   HPLC-gradient: 30-100% B in 3.25 min, flow=0.7 ml/min

HPLC Method H2 (Rt_(H2)):

-   HPLC-column dimensions: 3.0×30 mm-   HPLC-column type: Zorbax SB-C18, 1.8 μm-   HPLC-eluent: A) water+0.05 Vol.-% TFA; B) ACN+0.05 Vol.-% TFA-   HPLC-gradient: 0-100% B in 3.25 min, flow=0.7 ml/min

LCMS Method H3 (Rt_(H3)):

-   HPLC-column dimensions: 3.0×30 mm-   HPLC-column type: Zorbax SB-C18, 1.8 μm-   HPLC-eluent: A) water+0.05 Vol.-% TFA, B) ACN+0.05 Vol.-% TFA-   HPLC-gradient: 10-100% B in 3.25 min, flow=0.7 ml/min

UPLCMS Method H4 (Rt_(H4)):

-   HPLC-column dimensions: 2.1×50 mm-   HPLC-column type: Acquity UPLC HSS T3, 1.8 μm-   HPLC-eluent: A) water+0.05 Vol.-% formic acid+3.75 mM ammonium    acetate B) ACN+0.04 Vol.-% formic acid-   HPLC-gradient: 2-98% B in 1.4 min, 98% B 0.75 min, flow=1.2 ml/min-   HPLC-column temperature: 50° C.

UPLCMS Method H5 (Rt_(H5)):

-   HPLC-column dimensions: 2.1×50 mm-   HPLC-column type: Acquity UPLC HSS T3, 1.8 μm-   HPLC-eluent: A) water+0.1 Vol.-% formic acid, B) ACN+0.1% formic    acid-   HPLC-gradient: 10-95% B in 1.5 min, 1.0 min 95% B, flow=1.2 ml/min-   HPLC-column temperature: 50° C.

LCMS Method H6 (Rt_(H6)):

-   HPLC-column dimensions: 2.1×30 mm-   HPLC-column type: Ascentis Express C18, 2.7 μm-   HPLC-eluent: A) water+0.05 Vol.-% formic acid+0.05 ammonium    acetate, B) ACN+0.04 Vol.-% formic acid-   HPLC-gradient: 2-98% B in 1.4 min, 0.75 min 98% B, flow=1.2 ml/min-   HPLC-column temperature: 50° C.

LCMS Method H7 (Rt_(H7)):

-   HPLC-column dimensions: 4.0×20 mm-   HPLC-column type: Mercury MS Synergi, 2 μm-   HPLC-eluent: A) water+0.1 Vol.-% formic acid, B) ACN-   HPLC-gradient: 0.5 min 30% B, 30-95% B in 1 min, 0.9 min 95% B,    flow=2.0 ml/min-   HPLC-column temperature: 30° C.

LCMS Method H8 (Rt_(H8)):

-   HPLC-column dimensions: 4.0×20 mm-   HPLC-column type: Mercury MS Synergi, 2 μm-   HPLC-eluent: A) water+0.1 Vol.-% formic acid, B) ACN-   HPLC-gradient: 0.5 min 70% B, 70-100% B in 1 min, 0.9 min 100% B,    flow=2.0 ml/min-   HPLC-column temperature: 30° C.

HPLC Method H9 (Rt_(H9)):

-   HPLC-column dimensions: 4.6×150 mm-   HPLC-column type: Zorbax XDB-C18, 5 μm-   HPLC-eluent: A) water+0.01 Vol.-% TFA; B) ACN/MeOH 1:1-   HPLC-gradient: 1 min 30% B, 30-100% B in 5 min, 100-30% B in 4 min,    flow=1.0 ml/min-   HPLC-column temperature: 40° C.

HPLC Method H10 (Rt_(H10)):

-   HPLC-column dimensions: 4.6×150 mm-   HPLC-column type: Zorbax XDB-C18, 5 μm-   HPLC-eluent: A) water+0.01 Vol.-% TFA; B) ACN/MeOH 1:1-   HPLC-gradient: 1 min 5% B, 5-100% B in 5 min, 100-5% B in 4 min,    flow=1.0 ml/min-   HPLC-column temperature: 40° C.

LCMS Method H11 (Rt_(H11)):

-   HPLC-column dimensions: 3.0×30 mm-   HPLC-column type: Zorbax SB-C18, 1.8 μm-   HPLC-eluent: A) water+0.05 Vol.-% TFA; B) ACN+0.05 Vol.-% TFA-   HPLC-gradient: 70-100% B in 3.25 min, flow=0.7 ml/min

LCMS Method H12 (Rt_(H12)):

-   HPLC-column dimensions: 3.0×30 mm-   HPLC-column type: Zorbax SB-C18, 1.8 μm-   HPLC-eluent: A) water+0.05 Vol.-% TFA; B) ACN+0.05 Vol.-% TFA-   HPLC-gradient: 80-100% B in 3.25 min, flow=0.7 ml/min

LCMS Method H13 (Rt_(H13)):

-   HPLC-column dimensions: 3.0×30 mm-   HPLC-column type: Zorbax SB-C18, 1.8 μm-   HPLC-eluent: A) water+0.05 Vol.-% TFA; B) ACN+0.05 Vol.-% TFA-   HPLC-gradient: 40-100% B in 3.25 min, flow=0.7 ml/min

Example 1: 5-Bromo-pyridine-2-carboxylic acid[6-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]-oxazin-3-yl)-pyridin-2-yl]-amide

a) 5-(6-Bromo-pyridin-2-yl)-5-methyl-imidazolidine-2,4-dione

To a solution of 1-(6-bromo-pyridin-2-yl)-ethanone (CAS 49669-13-8, 8.75g, 43.7 mmol) and potassium cyanide (4.27 g, 65.6 mmol) in ethanol/water(40.0/26.7 ml) was added ammonium carbonate (21.02 g, 219.0 mmol). Thereaction mixture was stirred in an autoclave at 100° C. for 17 h, thendiluted with H₂O, 1M aq. NaHCO₃ soln. and EtOAc. The phases wereseparated and the aq. phase was reextracted with EtOAc, Et₂O and DCM.The combined org. phases were dried over Na₂SO₄, filtered andconcentrated to leave the title compound as a pale white solid that wasused in the next step without further purification.

HPLC Rt_(H4)=0.62 min; ESIMS: 270, 272 [(M+H)⁺]; ¹H NMR (400 MHz,DMSO-d₆): δ 10.86 (br s, 1H), 8.48 (s, 1H), 7.81 (m, 1H), 7.64 (d, 1H),7.57 (d, 1H), 1.68 (s, 3H).

b)4-(6-Bromo-pyridin-2-yl)-4-methyl-2,5-dioxo-imidazolidine-1,3-dicarboxylicacid di-tert-butyl ester

A solution of 5-(6-bromo-pyridin-2-yl)-5-methyl-imidazolidine-2,4-dione(22.8 g, 84.4 mmol), Boc₂O (58.8 ml, 55.3 g, 253.4 mmol) and DMAP (0.516g, 4.22 mmol) in THF (600 ml) was stirred at rt for 4 h. The reactionmixture was concentrated to dryness, then taken up with EtOAc andfiltered through silica. The silica cartridge was washed with EtOAc andTHF, the combined filtrates were concentrated to leave the titlecompound as a pale yellow solid that was used in the next step withoutfurther purification.

HPLC Rt_(H4)=1.23 min; ESIMS: 470, 472 [(M+H)⁺]; ¹H NMR (400 MHz,CD₃OD): δ 7.82 (m, 1H), 7.65 (m, 2H), 2.11 (s, 3H), 1.60 (s, 9H), 1.30(s, 9H).

c) 2-Amino-2-(6-bromo-pyridin-2-yl)-propionic acid

A solution of4-(6-bromo-pyridin-2-yl)-4-methyl-2,5-dioxo-imidazolidine-1,3-dicarboxylicacid di-tert-butyl ester (31.53 g, 67.0 mmol) in 2.5M aq. NaOH soln.(215 ml) was refluxed for 40 h. The reaction mixture was diluted withEtOAc (100 ml) and filtered. The filtrates were separated and the org.layer was washed with H₂O. The combined aq. layers were evaporated todryness to leave a solid that was suspended in MeOH (350 ml) and stirredfor 30 min. The suspension was filtered and the white precipitate waswashed with MeOH. The filtrates were evaporated to leave a pale orangesolid which was used for the next step without further purification.

HPLC Rt_(H4)=0.35-0.37 min; ESIMS: 245, 247 [(M+H)⁺]; ¹H NMR (400 MHz,CD₃OD): δ 7.60-7.51 (m, 2H), 7.36 (dd, 1H), 1.62 (s, 3H).

d) 2-Amino-2-(6-bromo-pyridin-2-yl)-propan-1-ol

To a suspension of 2-amino-2-(6-bromo-pyridin-2-yl)-propionic acid (25.5g, 72.8 mmol) and Boc₂O (33.8 ml, 31.8 g, 145.7 mmol) in acetonitrile(300 ml) and methanol (150 ml) was added tetramethylammonium hydroxide(65.1 ml of a 25% aq. soln., 182 mmol). The reaction was allowed to stirat rt for 6.5 h and was filtered. The filtrates were washed with MeOHand CH₃CN, then evaporated to leave an orange solid which was trituratedwith DCM and brine. The phases were separated and the aq. phase was 3×extracted with DCM. The combined org. phases were concentrated to leavecrude 2-(6-bromo-pyridin-2-yl)-2-tert-butoxycarbonylamino-propionic acidas a pale brown foam (HPLC Rt_(H4)=0.96-0.97 min, ESIMS: 345, 347[(M+H)⁺]).

To a suspension of2-(6-bromo-pyridin-2-yl)-2-tert-butoxycarbonylamino-propionic acid (14.1g, 40.8 mmol) in THF (150 ml) was added portionwise NaBH₄ (3.45 g, 90.0mmol) at 0° C. BF₃*Et₂O soln. (11.39 ml, 12.75 g, 90.0 mmol) was addeddropwise over a period of 15 min and the reaction mixture was allowed tostir for 17 h at rt. In order to react remaining starting material,NaBH₄ (1.0 g, 26.43 mmol), and BF₃*Et₂O soln. (3.3 ml, 26.43 mmol) wasadded at 0° C. and the reaction mixture was stirred at rt for another 23h. MeOH was added and the reaction mixture was stirred at 80° C. for 30min, then cooled to rt and filtered. The filtrates were evaporated toleave a white foam which was taken up with EtOAc and 1N aq. NaOH soln.The phases were separated and the aq. phase was extracted three timeswith EtOAc. The combined org. phases were dried over Na₂SO₄, filteredand concentrated to leave[1-(6-bromo-pyridin-2-yl)-2-hydroxy-1-methyl-ethyl]-carbamic acidtert-butyl ester in a mixture with2-amino-2-(6-bromo-pyridin-2-yl)-propan-1-ol. This mixture (7.5 g, 9.74mmol) was rebocylated using Boc₂O (5.65 ml, 5.31 g, 24.34 mmol) andtetramethylammonium hydroxide (65.1 ml of a 25% aq. soln., 182 mmol) inacetonitrile (100 ml). After stirring for 1.5 h at rt, the reactionmixture was quenched with H₂O and diluted with EtOAc. The phases wereseparated and the aq. layer was twice reextracted with EtOAc. Thecombined org. layers were dried over Na₂SO₄, filtered and the solventwas removed to leave a yellow solid that was without furtherpurification debocylated on a 8.1 g scale using 100 ml 4N aq. HCl. Thereaction mixture was stirred at rt for 17 h, concentrated and theresidue was taken up with H₂O and EtOAc. The phases were separated andthe org. phase was washed with H₂O. The combined aq. phases werebasified using 2N aq. NaOH soln. and then extracted with EtOAc. Thephases were separated and the aq. phase was reextracted twice withEtOAc. The combined org. phases were dried over Na₂SO₄, filtered andconcentrated to leave 2-amino-2-(6-bromo-pyridin-2-yl)-propan-1-ol as acolourless solid. HPLC Rt_(H4)=0.35 min; ESIMS: 231, 233 [(M+H)⁺]; ¹HNMR (400 MHz, DMSO-d₆): δ 7.73-7.63 (m, 2H), 7.45 (dd, 1H), 4.72-4.69(m, 1H), 3.58 (dd, 1H), 3.40 (dd, 1H), 2.00 (br s, 2H), 1.26 (s, 3H).

e)N-[1-(6-Bromo-pyridin-2-yl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide

To a solution of 2-amino-2-(6-bromo-pyridin-2-yl)-propan-1-ol (4.9 g,21.2 mmol) in DCM (50 ml) was added K₂CO₃ (5.86 g, 42.4 mmol). Thereaction mixture was cooled to 0° C. and 2-chloroacetyl chloride (2.55ml, 3.59 g, 31.8 mmol) was added dropwise. The reaction mixture wasallowed to warm to rt and to stir for 5 h. MeOH (20 ml) was added andstirring was continued at rt for 1 h. The reaction mixture was dilutedwith H₂O and DCM, the phases were separated and the aq. phase was twiceextracted with DCM. The combined org. phases were dried over Na₂SO₄,filtered and the solvent was removed to leaveN-[1-(6-bromo-pyridin-2-yl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamideas an orange oil. HPLC Rt_(H4)=0.73-0.77 min; ESIMS: 307, 309 [(M+H)⁺];¹H NMR (400 MHz, DMSO-d₆): δ 8.35 (s, 1H), 7.70-7.66 (m, 1H), 7.48 (dd,1H), 7.38 (dd, 1H), 5.05-5.02 (m, 1H), 4.14 (s, 2H), 3.68-3.66 (m, 2H),1.55 (s, 3H).

f) 5-(6-Bromo-pyridin-2-yl)-5-methyl-morpholin-3-one

To a solution ofN-[1-(6-bromo-pyridin-2-yl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamidein tert-butanol (90 ml) was added KOtBu and the reaction mixture wasstirred at rt for 4 h. The reaction mixture was quenched with H₂O anddiluted with EtOAc. The phases were separated and the aq. phase wastwice extracted with EtOAc. The combined org. phases were washed withbrine, dried over Na₂SO₄, filtered and the solvent was removed to leavethe title compound as a pale yellow solid. HPLC Rt_(H4)=0.73 min; ESIMS:271, 273 [(M+H)⁺];

¹H NMR (400 MHz, DMSO-d₆): δ 8.72 (s, 1H), 7.82-7.78 (m, 1H), 7.57-7.51(m, 2H), 4.10 (d, 2H), 4.00 (d, 1H), 3.65 (d, 1H), 1.42 (s, 3H).

g) 5-(6-Bromo-pyridin-2-yl)-5-methyl-morpholine-3-thione

A mixture of 5-(6-bromo-pyridin-2-yl)-5-methyl-morpholin-3-one (4.65 g,17.15 mmol) and P₂S₅ (4.57 g, 20.58 mmol) in pyridine (60 ml) wasstirred at 80° C. under N₂ for 6 h. The reaction mixture was cooled tort and diluted with 0.5N aq. HCl and EtOAc. The phases were separatedand the aq. phase was twice extracted with EtOAc. The combined org.phases were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The title compound was obtained as a pale yellow solidafter flash chromatography on silica gel (cyclohexane/EtOAc 100:0 to75:25). HPLC Rt_(H4)=0.89 min; ESIMS: 287, 289 [(M H)⁺]; ¹H NMR (400MHz, DMSO-d₆): δ 11.15 (s, 1H), 7.86-7.82 (m, 1H), 7.61 (dd, 1H), 7.39(dd, 1H), 4.44-4.34 (d, 2H), 4.13 (d, 1H), 3.74 (d, 1H), 1.52 (s, 3H).

h)5-(6-Bromo-pyridin-2-yl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine

A mixture of 5-(6-bromo-pyridin-2-yl)-5-methyl-morpholine-3-thione (1.4g, 4.88 mmol) in 7N NH₃/MeOH (20.89 ml, 146 mmol) was stirred at 50° C.for 3 d in an autoclave. The reaction mixture was evaporated to drynessand purified by FC (gradient cyclohexane:EtOAc 75:25 to 50:50, then +10%Et₃N, finally MeOH+10% Et₃N) to obtain the crude title compound that wasfurther purified by washing with DCM. HPLC Rt_(H4)=0.54 min; ESIMS: 270,272 [(M+H)⁺]; ¹H NMR (400 MHz, DMSO-d₆): δ 8.51 (br s, 2H), 7.83-7.79(m, 1H), 7.63-7.61 (m, 2H), 4.45 (s, 2H), 4.11 (d, 1H), 3.84 (d, 1H),1.51 (s, 3H).

i)[5-(6-Bromo-pyridin-2-yl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

A suspension of5-(6-bromo-pyridin-2-yl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine(1.100 g, 4.07 mmol), Boc₂O (1.229 ml, 1.155 g, 5.29 mmol) and DIPEA(1.067 ml, 0.789 g, 6.11 mmol) in DCM (30 ml) was stirred at rt for 20h. The reaction mixture was diluted with H₂O and DCM. The phases wereseparated and the aq. phase was twice reextracted with DCM. The combinedorg. phases were washed with brine, dried over Na₂SO₄, filtered andconcentrated to yield the title compound as a colourless solid that wasused in the next step without further purification. HPLC Rt_(H4)=0.92min; ESIMS: 370, 372 [(M+H)⁺].

j) (+)- and(−)-5-(6-Amino-pyridin-2-yl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

A mixture of[5-(6-Bromo-pyridin-2-yl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (986 mg, 2.66 mmol), cyclohexanedimethyldiamine(0.420 ml, 379 mg, 2.66 mmol), sodium ascorbate (211 mg, 1.07 mmol),NaN₃ (1385 mg, 21.31 mmol) and CuI (203 mg, 1.07 mmol) in ethanol/water(22.0/8.8 ml) was degassed with N₂ in a dry ice/EtOH bath. The reactionmixture was then stirred at 45° C. for 4 h. The reaction mixture wasallowed to warm to rt and filtered through hyflo, rinsed with EtOAc andconcentrated. Flash chromatography on silica gel (cyclohexane/EtOAcgradient 0-3 min 100:0, 3-25 min 60:40, 40-52 min 50:50) yielded thetitle compound. HPLC Rt_(H4)=0.60, 0.66 min; ESIMS: 305 [(M −H)⁺]; ¹HNMR (400 MHz, DMSO-d₆): δ 7.77-7.73 (m, 1H), 6.81-6.76 (m, 2H),4.71-4.63 (m, 1H), 4.70-4.56 (m, 2H), 4.06-3.96 (m, 2H), 1.69 (s, 3H),1.51 (s, 9H).

Racemic5-(6-amino-pyridin-2-yl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester was separated into the pure enantiomers bypreparative chiral HPLC (column: Chiralpak AS; solvent:n-heptane/ethanol/isopropylamine=80:12:8; flow: 70 ml/min; detection at220 nm). Enantiomer 1: [α]_(D)=−138.5° (c=1.00, MeOH). Enantiomer 2:[α]_(D)=+141.5° (c=1.03, MeOH). (−)-Enantiomer 1 was used for thefollowing steps, its configuration was assigned (R) in analogy tosimilar structures of which the configuration has been determined byx-ray crystallography.

k)((R)-5-{6-[(5-Bromo-pyridine-2-carbonyl)-amino]-pyridin-2-yl}-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester

To a solution of 5-bromopyridine-2-carboxylic acid (34.5 mg, 0.171 mmol)in DCM (2 ml) was added 1-chloro-N,N,2-trimethylpropenylamine (0.045 ml,45.7 mg, 0.342 mmol) and the reaction mixture was stirred at 0° C. for 1h. The reaction mixture was then added dropwise to a dry solution of(−)-5-(6-amino-pyridin-2-yl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (enantiomer 1 from procedure step j) above, 47.6mg, 0.155 mmol) and NEt₃ (0.048 ml, 34.6 mg, 0.342 mmol) in DCM (2 ml)at 0° C. The reaction mixture was allowed to warm to rt and to stir for20 min at rt. The reaction mixture was diluted with DCM and quenchedwith H₂O. The phases were separated and the aq. phase was extracted withDCM. The combined org. phases were washed with brine, dried over Na₂SO₄,filtered and twice purified by HPLC (Alltech Grom Saphir65 Si 10 μMcolumn 150×30 mm, gradient 1 n-heptane:EtOAc 0-1.2 min 85:15, 1.2-9 min0:100, 9-12 min 0:100, gradient 2 n-heptane:EtOAc:MeOH 0-1.2 min47:50:3, 1.2-9 min 0:60:40, 9-12 min 0:60:40, flow 50 ml/min, detection254 nm]. HPLC Rt_(H4)=1.10 min; ESIMS: 490, 492 [(M+H)⁺].

l) 5-Bromo-pyridine-2-carboxylic acid[6-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]-oxazin-3-yl)-pyridin-2-yl]-amide

To a solution of5-{6-[(5-bromo-pyridine-2-carbonyl)-amino]-pyridin-2-yl}-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester (43 mg, 0.088 mmol) in DCM (270 μl) was added TFA(270 μl, 400 mg, 3.51 mmol) and the reaction mixture was stirred at rtfor 1 h. The reaction mixture was quenched with 1M aq. NaHCO₃ soln. anddiluted with DCM. The phases were separated and the aq. phase was twicereextracted with DCM. The combined org. phases were dried over Na₂SO₄,filtered, concentrated and purified by manual flash chromatography(NH₃-deactivated silica gel, hexane:DCM:MeOH 10:10:1 then DCM:MeOH 10:1,then +0.1% NH₃ and finally MeOH+1% NH₃) to yield the title compound as acolourless solid. To a solution of the free base in DCM was added 1 eq.2N HCl/Et₂O and the resulting hydrochloride salt was collected. HPLCRt_(H4)=0.76 min; ESIMS: 390, 392 [(M+H)⁺]; ¹H NMR (400 MHz, CD₃OD): δ8.88 (d, 1H), 8.38 (d, 1H), 8.33 (dd, 1H), 8.27-8.24 (m, 1H), 8.24-7.98(m, 1H), 7.33 (d, 1H), 4.69 (d, 1H), 4.67 (d, 1H), 4.30 (d, 1H), 4.11(d, 1H), 1.78 (s, 3H).

Example 2: 5-Bromo-pyridine-2-carboxylic acid[6-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]-oxazin-3-yl)-pyridin-2-yl]-amide

The racemate of Example 1 can be prepared by a procedure analogous tothat used in Example 1 completing the synthesis using the racemicmixture obtained in step j) of Example 1 and has the same analyticaldata.

Example 3:5-{6-[(5-Chloro-pyridine-2-carbonyl)-amino]-pyridin-2-yl}-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl-ammoniumtrifluoro acetate

a) 2-(6-Bromo-pyridin-2-yl)-malonic acid diethyl ester

Lithium diisopropylamide (2.0 M solution in heptane/THF/ethyl benzene,581.3 ml) was taken in dry THF (400 mL) and cooled to −78° C.2-Bromo-6-methyl pyridine (50.0 g, 296.64 mmol) was added slowly to theLDA solution at the same temperature for 15 min., allowed to stirconstantly for 30 min. Ethylchloroformate (94.62 g, 871.94 mmol) in dryTHF (50 ml) was then added to the stirred contents drop wise and allowedthe reaction mass to stir at −78° C. for 2 h. Reaction mixture wasquenched with saturated ammonium chloride solution and product formedwas extracted with ethyl acetate by washing with water, brine and driedover anhy. Na₂SO₄. Organic layer was concentrated under reduced pressureand the crude product was purified by column chromatography using 10%ethyl acetate in hexane to furnish title compound as a brown coloredliquid. Yield=65.0 g (71.4%). TLC (10% ethyl acetate in hexane)R_(f)=0.31; LCMS: Rt_(H8)=1.866; [M+1]=315.8 and 317.9; HPLC:Rt_(H9)=4.636 min (48%); ¹H NMR (400 MHz, CDCl₃): δ 7.587 (t, 1H), 7.47(d, 1H), 7.27 (d, 1H), 3.91 (s, 1H), 4.25-4.09 (m, 4H), 1.24 (t, 6H).

b) (6-Bromo-pyridin-2-yl)-acetic acid

2-(6-Bromo-pyridin-2-yl)-malonic acid diethyl ester (64.0 g, 202.4 mmol)was added to a solution of potassium carbonate (279.8 g, 2024 mmol) inwater (400 ml) at rt and the reaction mixture was heated to reflux at100° C. for 36 h. The reaction mixture was treated with sat. ammoniumchloride solution and the product formed was extracted with ethylacetate (3×800 ml), washed with brine (10 ml). Organic layer wasconcentrated under reduced pressure to obtain title compound as a palebrown solid. Yield=34.0 g (77.7%). TLC (50% ethyl acetate in hexane)R_(f)=0.11; LCMS: Rt_(H8)=0.45; [M+1]=216.0 and 218.0.

c) (6-Bromo-pyridin-2-yl)-acetic acid ethyl ester

To a solution of (6-bromo-pyridin-2-yl)-acetic acid (34.0 g, 158.14mmol) in ethanol (300 ml) was added conc. H₂SO₄ (5.0 ml) and heated toreflux for 12 h. The reaction mixture was cooled to rt and concentratedunder reduced pressure to dryness. Water was added to the residue andthe product was extracted with ethyl acetate. Organic layer was washedwith brine, dried over anhy. Na₂SO₄ and concentrated under reducedpressure to furnish the crude product. Column chromatographypurification furnished the title compound as a brown liquid. Yield=31.2g (82%). TLC (20% ethyl acetate in hexane) R_(f)=0.51; LCMS:Rt_(H7)=0.996, [M+1]⁺=244.0 and 246.0; HPLC: Rt_(H9)=3.87 min (97.2%);¹H NMR (400 MHz, CDCl₃): δ 7.53 (t, 1H), 7.39 (d, 1H), 7.28 (d, 1H),4.19 (q, 2H), 3.83 (s, 2H), 1.25 (t, 3H).

d) 2-(6-Bromo-pyridin-2-yl)-3-hydroxy-2-hydroxymethyl-propionic acidethyl ester

To the solution of para formaldehyde (9.6 g, 319.55 mmol) and sodiumethoxide (0.87 g, 12.784 mmol) in dry THF (250 ml) was added(6-bromo-pyridin-2-yl)-acetic acid ethyl ester (31.2 g, 127.82 mmol) at0° C. to −10° C. and allowed the reaction mixture to stir at sametemperature for 4 h. Solids formed in the reaction mixture were filteredand washed with ethyl acetate and the filtrate was concentrated toobtain crude product as a brown liquid. Yield=30.0 g (crude). TLC (30%ethyl acetate in hexane) R_(f)=0.28; LCMS: Rt_(H8)=0.702, M+1=304.0 and306.0.

e)2-(6-Bromo-pyridin-2-yl)-3-methoxymethoxy-2-methoxymethoxymethyl-propionicacid ethyl ester

To the solution of2-(6-bromo-pyridin-2-yl)-3-hydroxy-2-hydroxymethyl-propionic acid ethylester (30.0 g, 98.638 mmol) in dry THF (250 ml) was added tetrabutylammonium bromide (15.8 g, 49.319 mmol) and di-isopropyl ethyl amine(127.47 g, 163.0 ml) followed by methoxymethyl chloride was added dropwise at rt. Resultant reaction contents were refluxed at 65° C. for 3 hand cooled to rt. Reaction mixture was concentrated under reducedpressure and purified by column chromatography over silica gel using 10%ethyl acetate in hexane to furnish title compound as a brown liquid.Yield=20.4 g (52%). TLC (30% ethyl acetate in hexane) R_(f)=0.55; LCMS:Rt_(H7)=1.639, [M+1]⁺=392.0 and 394.0; ¹H NMR (400 MHz, CDCl₃): δ 7.49(t, 1H), 7.35 (d, 1H), 7.22 (d, 1H), 4.62-4.47 (m, 4H), 4.24-4.16 (m,6H), 3.25 (s, 6H), 1.23 (t, 3H).

f)2-(6-Bromo-pyridin-2-yl)-3-methoxymethoxy-2-methoxymethoxymethyl-propionicacid

Lithium hydroxide (10.69 g, 254.95 mmol) was added to a solution of2-(6-bromo-pyridin-2-yl)-3-methoxymethoxy-2-methoxymethoxymethyl-propionicacid ethyl ester (20.0 g, 50.99 mmol) in ethanol (100 ml) and water (100ml) at rt and the reaction mixture was allowed to stir overnight. Thereaction mass was concentrated under reduced pressure and acidified withdilute HCl and at 0° C. The product was extracted with ethyl acetate,washed with minimum amount of brine. Organic layer was concentratedunder reduced pressure to obtain title compound as a brown liquid.Yield=18.0 g. TLC (50% ethyl acetate in hexane) R_(f)=0.05; LCMS:Rt_(H8)=1.383, [M+1]=364.0 and 366.0; HPLC: Rt_(H9)=3.844 min (49%) and3.885 min. (22%).

g)1-(6-Bromo-pyridin-2-yl)-2-methoxymethoxy-1-methoxymethoxymethyl-ethylamine

To a suspension of2-(6-bromo-pyridin-2-yl)-3-methoxymethoxy-2-methoxymethoxymethyl-propionicacid (18.0 g) in toluene (150 ml) diphenyl phosphoryl azide (4.08 g,148.27 mmol) and triethylamine (14.97 g [20.6 ml], 148.27 mmol) wereadded at rt and stirred at 100° C. for 15 h. Reaction mixture was cooledto rt and concentrated under reduced pressure. The residue obtained wasdissolved in THF (600 ml) and 20% NaOH solution was added at rt andstirred for 1 h. Solvent was removed under reduced pressure and theproduct formed was extracted with ethyl acetate. Organic layer waswashed with brine, followed by dried over MgSO₄. The organic portion wasconcentrated under reduced pressure and column chromatographicpurification of the crude product using 35% ethyl acetate in hexanefurnished title compound as a brown liquid. Yield=15.0 g (88% [2steps]). TLC (70% ethyl acetate in hexane) R_(f)=0.51; LCMS:Rt_(H7)=0.28, [M+1]=335.0 and 337.0.

h)N-[1-(6-Bromo-pyridin-2-yl)-2-methoxymethoxy-1-methoxymethoxymethyl-ethyl]-2-chloro-acetamide

To a solution of1-(6-bromo-pyridin-2-yl)-2-methoxymethoxy-1-methoxymethoxymethyl-ethylamine(15.0 g, 44.75 mmol) in DCM (150 ml) was added aqueous Na₂CO₃ solution(10.91 g, 102.925 mmol in water, 30 ml) was added at 0° C. and stirredfor 10 min. Chloroacetylchloride (5.56 g, 49.225 mmol) was added to theresultant reaction mixture at 0° C. stirring continued for 1 h atambient temperature. Reaction mixture was diluted with DCM (˜1 l), andworked up the reaction mixture by washing with water, brine and driedover anhy. Na₂SO₄. Organic layer was separated and concentrated underreduced pressure to obtain title compound as a brown liquid. Yield=9.0 g(48%). TLC (50% ethyl acetate in hexane) R_(f)=0.54; LCMS:Rt_(H7)=1.341, [M+1]=411.0 and 413.0; HPLC: Rt_(H9)=4.27 min (50.4%); ¹HNMR (400 MHz, CDCl₃): δ 8.11 (d, 1H), 7.57-7.52 (m, 1H), 7.46-7.37 (m,2H), 4.59-4.52 (m, 4H), 4.23-4.17 (m, 4H), 4.09-4.04 (m, 2H), 3.21 (s,6H).

i)N-[1-(6-Bromo-pyridin-2-yl)-2-hydroxy-1-hydroxymethyl-ethyl]-2-chloro-acetamide

To a solution ofN-[1-(6-bromo-pyridin-2-yl)-2-methoxymethoxy-1-methoxymethoxymethyl-ethyl]-2-chloro-acetamide(9.0 g, 21.861 mmol) in ethanethiol (30 ml) and BF₃.Et₂O (9.3 g, 141.93mmol) was added at 0° C. and stirred for 10 min. Stirring was continuedfor 3 h at rt. Reaction mixture was quenched with saturated NaHCO₃solution and the product formed was extracted with ethyl acetate.Organic layer was separated and washed with brine solution, followed bydrying over anhydrous Na₂SO₄. Organic layer was concentrated underreduced pressure and purified by column chromatography using 2% methanolin chloroform to obtain title compound as a brown liquid. Yield=5.5 g(77%). TLC (10% methanol in chloroform) R_(f)=0.51; LCMS: Rt_(H8)=0.916,[M+1]=322.9 and 324.8; HPLC Rt_(H9)=5.931 min (89%); ¹H NMR (400 MHz,CDCl₃): δ 8.27 (s, 1H), 7.56 (t, 1H), 7.42-7.39 (m, 2H), 4.38 (s, 2H),4.09-4.07 (m, 4H), 3.95 (d, 2H).

j) 5-(6-Bromo-pyridin-2-yl)-5-hydroxymethyl-morpholin-3-one

To the solution ofN-[1-(6-bromo-pyridin-2-yl)-2-hydroxy-1-hydroxymethyl-ethyl]-2-chloro-acetamide(5.4 g, 16.69 mmol) in t-BuOH (80 ml) was added t-BuOK (2.06 g, 18.38mmol) at rt followed by sodium iodide (0.25 g, 1.669 mmol) and allowedthe reaction mixture to stir at 90° C. for 1 h. The reaction mixture wasconcentrated under reduced pressure and the residue obtained was treatedwith water. Compound present in the residue was extracted with ethylacetate (2×100 ml). Organic portion was washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure to obtain gummy compound.Further trituration of the formed product with n-pentane (5.0 ml) anddiethyl ether (5.0 ml) furnished title compound as a pale yellow gummycompound. Yield=3.3 g (68.8%). TLC (50% ethyl acetate in hexane)R_(f)=0.21; LCMS: Rt_(H8)=0.155, [M+1]=286.9 and 288.8; HPLCRt_(H9)=3.03 min (69.8%); ¹H NMR (400 MHz, CDCl₃): δ 8.40 (s, 1H), 7.79(t, 1H), 7.57 (d, 2H), 5.11 (s, 1H), 4.15 (d, 1H), 3.99 (d, 2H), 3.88(d, 1H), 3.71-3.60 (m, 2H).

k) 5-(6-Bromo-pyridin-2-yl)-5-fluoromethyl-morpholin-3-one

To a solution of5-(6-bromo-pyridin-2-yl)-5-hydroxymethyl-morpholin-3-one (2.8 g, 9.756mmol) in dry THF (30 ml), diethylamino sulfur trifluoride (4.72 g,29.268 mmol) was added at rt and stirring continued for 4 h. Na₂CO₃ wasthen added to the resultant reaction mixture and stirred for further 30min. The reaction mixture was concentrated under reduced pressure andthe product was extracted with ethyl acetate. Organic layer was washedwith brine, dried over anhy. Na₂SO₄ and concentrated under reducedpressure to obtain crude compound as gummy residue. Purification of thecrude product with 45% ethyl acetate in hexane solvent system furnishedthe title compound as off-white solid. Yield=1.15 g (40%). TLC (70%ethyl acetate in hexane) R_(f)=0.49; LCMS: Rt_(H7)=0.383, [M+1]⁺=289 and289; HPLC Rt_(H9)=3.27 min (84%); ¹H NMR (400 MHz, CDCl₃): δ 7.62 (t,1H), 7.49 (dd, 1H), 7.32 (d, 1H), 7.09 (br. s, 1H), 4.92 (dd, 1H), 4.52(dd, 1H), 4.32-4.17 (m, 3H), 3.98-3.93 (dd, 1H); ¹⁹F NMR (376.2 MHz): δ−255.65 (t, 1F).

l) 5-Chloro-pyridine-2-carboxylic acid[6-(3-fluoromethyl-5-oxo-morpholin-3-yl)-pyridin-2-yl]-amide

A mixture of 4,5-Bis(diphenyl phosphino)-9,9-dimethyl xanthene (0.04 g,0.069 mmol), tris(dibenzylidene-acetone) di palladium(0) (0.032 g, 0.035mmol) and cesium carbonate (0.678 g, 2.083 mmol) were taken in1,4-dioxane and degassed with argon for 10 min.5-(6-Bromo-pyridin-2-yl)-5-fluoromethyl-morpholin-3-one (0.2 g, 0.694mmol) followed by 5-chloropicolinamide (0.119 g, 0.764 mmol) were addedto the resultant reaction mixture and degassed with argon for further 5min. Reaction mixture was then heated at 80° C. for 16 h and cooled tort. Reaction contents were treated with water and product was extractedwith ethyl acetate, washed with brine and dried over anhy. Na₂SO₄. Theorganic layer was concentrated under reduced pressure to obtain liquidwhich was triturated with n-pentane to furnish title compound as aoff-white solid. Yield=0.24 g (crude). TLC (50% ethyl acetate in hexane)R_(f)=0.45; LCMS: Rt_(H8)=1.215, [M+1]=365.1 and 366.9; HPLCRt_(H9)=4.367 min (53%).

m) 5-Chloro-pyridine-2-carboxylic acid[6-(3-fluoromethyl-5-thioxo-morpholin-3-yl)-pyridin-2-yl]-amide

To a solution of 5-chloro-pyridine-2-carboxylic acid[6-(3-fluoromethyl-5-oxo-morpholin-3-yl)-pyridin-2-yl]-amide (0.24 g,0.658 mmol) in THF (10.0 ml), Lawesson's reagent (0.798 g, 1.974 mmol)was added at rt and heated at reflux temperature for 24 h. Reaction masswas concentrated under reduced pressure. The crude compound was directlypurified by column chromatography using 23% ethyl acetate in hexane tofurnish title compound as off-white solid. Yield=0.19 g (72% [2 steps]).TLC (50% ethyl acetate in hexane) R_(f)=0.71; LCMS: Rt_(H8)=1.578,[M+1]⁺=381.1 and 382.9.

n)5-{6-[(5-Chloro-pyridine-2-carbonyl)-amino]-pyridin-2-yl}-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl-ammoniumtrifluoro acetate

To a solution of 5-chloro-pyridine-2-carboxylic acid[6-(3-fluoromethyl-5-thioxo-morpholin-3-yl)-pyridin-2-yl]-amide (0.19 g,0.499 mmol) in methanol (2.0 ml), 10% ammonia in methanol (8.0 ml) wasadded at 0° C. in a sealed tube and stirred at rt for 24 h. Reactionmass was concentrated under reduced pressure and directly purified bypreparative HPLC. Conditions: column: C18-ZORBAX 21.2×150 mm; 5 μm.mobile phase: 0.1% TFA in water (A)/ACN; flow: 20 ml/min. Yield: 86 mg(36%). M.P: 216-218° C. TLC (20% methanol in chloroform) R_(f)=0.45;LCMS: Rt_(H8)=0.194 [M+1]=364.0 and 366.1; HPLC Rt_(H9)=3.222 min(98.7%); ¹H NMR (400 MHz, DMSO-d₆): δ 10.85 (s, 1H), 10.37 (s, 1H), 9.37(s, 1H), 8.50-8.79 (m, 2H), 8.31-8.23 (m, 3H), 8.06 (t, 1H), 7.37 (d,1H), 4.96 (dd, 1H), 4.85 (dd, 1H), 4.62 (dd, 2H), 4.25-4.16 (m, 2H).Product formation was also confirmed by 2D NMR-ROESY.

Examples 4 to 7

The compounds listed in Table 4 were prepared by a procedure analogousto those used in Example 3.

TABLE 4 MS ¹H-NMR [m/z; Example Compound (δ; DMSO-d₆) (M + 1)⁺] 4

  5-{6-[(5-Bromo-pyridine-2-carbonyl)-amino]-pyridin-2-yl}-5-fluoromethyl-5,6-dihydro-2H- [1,4]oxazin-3-yl-ammoniumtrifluoro acetate 10.74 (s, 1H), 10.34 (s, 1H), 9.35 (s, 1H), 8.92 (t,1H), 8.69 (s, 1H), 8.39 (dd, 1H), 8.29 (dd, 1H), 8.17 (dd, 1H), 8.05 (t,1H), 7.36 (d, 1H), 4.96 (dd, 1H), 4.86 (dd, 1H), 4.62 (dd, 2H), 4.25-4.15 (m, 2H). LCMS: Rt_(H8) = 0.239 [M + 1] = 408.0, 410.0 5

  5-{6-[(5-Cyano-3-methyl-pyridine-2-carbonyl)-amino]-pyridin-2-yl}-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl-ammonium trifluoro acetate 9.01 (s, 1H),8.43 (s, 1H), 8.11 (d, 1H), 7.874 (t, 1H), 7.40 (d, 1H), 4.59-4.45 (m,2H), 4.03-3.85 (m, 6H), 2.61 (s, 3H), 1.89 (s, 3H). LCMS: Rt_(H8) =0.127; [M + 1] = 369.4 6

  5-{6-[(4,6-Dideutero-5-chloro-3-trideuteromethyl-pyridine-2-carbonyl)-amino]-pyridin-2-yl}-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl-ammonium trifluoro acetate 10.80 (s,1H), 10.54 (s, 1H), 9.35 (s, 1H), 8.76 (s, 1H), 8.25 (d, 1H), 8.02 (t,1H), 7.33 (d, 1H), 4.99-4.76 (m, 2H), 4.61 (m, 2H), 4.18 (t, 2H). LCMS:Rt_(H8) = 0.208; [M + 1] = 383.3 7

  5-{6-[(5-Thiocarbamoyl-pyridine-2-carbonyl)-amino]-pyridin-2-yl]-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl-ammonium trifluoro-acetate 10.82 (s, 1H),10.46 (s, 1H), 10.33 (s, 1H), 9.96 (s, 1H), 9.36 (s, 1H), 90.1-9.09 (m,1H), 8.73 (s, 1H), 8.44 (dd, 1H), 8.28 (dd, 2H), 8.06 (t, 1H), 7.37 (d,1H), 5.03- 4.78 (m, 2H), 4.61 (dd, 2H), 4.26-4.16 (m, 2H). LCMS: Rt_(H7)= 0.153; [M + 1] = 389.1

Example 8: 5-Cyano-3-methyl-pyridine-2-carboxylic acid[6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoro-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide

a)4-(6-Bromo-pyridin-2-yl)-4-methyl-2-oxo-2lambda*4*-[1,2,3]oxathiazolidine-3-carboxylicacid tert-butyl ester

To an at 0° C. precooled solution of thionyl chloride (3.42 ml, 5.57 g,46.8 mmol) in pyridine (9.46 ml, 9.25 g, 117.0 mmol) was added dropwisea solution of[1-(6-bromo-pyridin-2-yl)-2-hydroxy-1-methyl-ethyl]-carbamic acidtert-butyl ester (see Example 1 step d), 7.75 g, 23.4 mmol) in DCM (230ml). The reaction mixture was allowed to stir for 1 h at rt, then 0.5 Naq. HCl and DCM were added, the phases were separated and the aq. phasewas twice reextracted with DCM. The combined org. phases were washedwith brine, dried over Na₂SO₄, filtered and concentrated to leave thetitle compound (mixture of diastereomers) as an orange solid. HPLCRt_(H4)=1.16, 1.20 min (diastereomers); ESIMS: 377, 379 [(M H)⁺].

b)4-(6-Bromo-pyridin-2-yl)-4-methyl-2,2-dioxo-2lambda*6*-[1,2,3]oxathiazolidine-3-carboxylicacid tert-butyl ester

To a solution of4-(6-bromo-pyridin-2-yl)-4-methyl-2-oxo-2lambda*4*-[1,2,3]oxathiazolidine-3-carboxylicacid tert-butyl ester (8.83 g, 23.4 mmol) in acetonitrile (60 ml) andH₂O (30.0 ml) was added RuCl₃ hydrate (0.971 g, 4.68 mmol) and NaIO₄(10.01 g, 46.8 mmol). The reaction mixture was stirred at 0° C. for 2 h.H₂O and DCM were added, the phases were separated and the aq. phase wastwice reextracted with DCM. The combined org. phases were washed withbrine, dried over Na₂SO₄, filtered and concentrated. The residue wasdissolved in DCM and filtered through silica gel, the filtrate wasevaporated and the residue was triturated with TBME (10 ml) and n-hexane(100 ml). The resulting precipitate was filtered and washed withn-hexane to yield the title compound as a colourless crystalline solid.HPLC Rt_(H4)=1.16 min; ESIMS: 393, 395 [(M+H)⁺]; ¹H NMR (400 MHz,CDCl₃): δ 7.63-7.59 (m, 1H), 7.47-7.42 (m, 2H), 4.73 (d, 1H), 4.47 (d,1H), 2.00 (s, 3H), 1.52 (s, 9H).

c)(R)-2-[(RS)-2-(6-Bromo-pyridin-2-yl)-2-tert-butoxycarbonylamino-propoxy]-3,3,3-trifluoro-2-methyl-propionicacid ethyl ester

At 0° C., NaH (0.508 g of a 60% dispersion in mineral oil, 12.69 mmol)was added to a solution of4-(6-bromo-pyridin-2-yl)-4-methyl-2,2-dioxo-2lambda*6*-[1,2,3]oxathiazolidine-3-carboxylicacid tert-butyl ester (3.84 g, 9.76 mmol) and(R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid ethyl ester (2.54g, 13.67 mmol) in DMF (10 ml, soln. predried over 4 Å mol. sieves). Thereaction mixture was allowed to stir at rt for 30 min, then at 60° C.for 17 h. The reaction mixture was quenched with H₂O and diluted with 1Naq. HCl and EtOAc. The phases were separated and the aq. phase was twicereextracted with EtOAc. The combined org. phases were washed withbrines, dried over Na₂SO₄, filtered and concentrated. Flashchromatography on silica gel (cyclohexane: EtOAc, gradient 0-5 min100:0, 5-30 min 90:10, 30-40 min 90:10, 40-50 min 80:20, 50-55 min80:20) yielded the title compound (diastereomer mixture) as a clear oil.HPLC Rt_(H4)=1.39 min; ESIMS: 499, 501 [(M+H)⁺].

d)[(RS)-1-(6-Bromo-pyridin-2-yl)-2-((R)-1-carbamoyl-2,2,2-trifluoro-1-methyl-ethoxy)-1-methyl-ethyl]-carbamicacid tert-butyl ester

A solution of(R)-2-[(RS)-2-(6-bromo-pyridin-2-yl)-2-tert-butoxycarbonylamino-propoxy]-3,3,3-tri-fluoro-2-methyl-propionicacid ethyl ester (3.0 g, 6.01 mmol) in 7N NH₃/MeOH (6.5 ml) was stirredin a sealed glass vial at 55° C. for 72 h. The reaction mixture wasconcentrated to leave the title compound as a colourless solid that wasused in the next step without further purification. HPLC Rt_(H4)=1.12,1.14 min (diastereomers); ESIMS: 470, 472 [(M+H)⁺].

e)[(RS)-1-(6-Bromo-pyridin-2-yl)-2-((R)-1-cyano-2,2,2-trifluoro-1-methyl-ethoxy)-1-methyl-ethyl]-carbamicacid tert-butyl ester

To an at 0° C. percooled solution of[(RS)-1-(6-bromo-pyridin-2-yl)-2-((R)-1-carbamoyl-2,2,2-trifluoro-1-methyl-ethoxy)-1-methyl-ethyl]-carbamicacid tert-butyl ester (2.18 g, 4.64 mmol) and NEt₃ (1.615 ml, 1.173 g,11.59 mmol) in DCM (30 ml) was added dropwise TFAA (0.773 ml, 1.168 g,5.56 mmol). After stirring for 5 min at 0° C., then for 1 h at rt thereaction mixture was diluted with sat. aq. Na₂CO₃ soln. and with DCM.The phases were separated and the aq. phase was twice reextracted withDCM. The combined org. phases were dried over Na₂SO₄, filtered andconcentrated to leave a pale yellow oil which was stirred with 7NNH₃/MeOH for 5 min. The mixture was evaporated to dryness and purifiedby flash chromatography (cyclohexane: EtOAc 0-3 min 100:0, 3-35 min65:35) to yield the title compound as a clear oil.

HPLC Rt_(H4)=1.30 min; ESIMS: 452, 454 [(M+H)⁺]; ¹H NMR (400 MHz,CDCl₃): δ 7.59-7.53 (m, 1H), 7.42-7.36 (m, 2H), 5.66 (br s, 1H),4.41-4.31 (m, 1H), 4.25-4.18 (m, 1H), 1.71 (d, 3H), 1.66 (d, 3H), 1.43(s, 9H).

f)(R)-2-[(RS)-2-Amino-2-(6-bromo-pyridin-2-yl)-propoxy]-3,3,3-trifluoro-2-methyl-propionitrile

A solution of[(RS)-1-(6-bromo-pyridin-2-yl)-2-((R)-1-cyano-2,2,2-trifluoro-1-methyl-ethoxy)-1-methyl-ethyl]-carbamicacid tert-butyl ester (0.456 g, 1.008 mmol) and TFA (1.554 ml, 2.299 g,20.17 mmol) in DCM (5 ml) was stirred at rt for 30 min, concentrated andtriturated with 7N NH₃/MeOH at rt for 20 min and again concentrated togive the title compound that was used for the next step without furtherpurification. HPLC Rt_(H4)=0.69, 0.73 min (diastereomers); ESIMS: 352,354 [(M+H)⁺].

g)(2R,5RS)-5-(6-Bromo-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine

A suspension of(R)-2-[(RS)-2-amino-2-(6-bromo-pyridin-2-yl)-propoxy]-3,3,3-trifluoro-2-methyl-propionitrile(0.688 g, 1.172 mmol), N-acetyl-L-cysteine (0.383 g, 2.344 mmol) andK₂CO₃ (0.356 g, 2.560 mmol) in abs. EtOH (4 ml) was stirred at 80° C.for 18 h. The reaction mixture was quenched with 10% aq. K₂CO₃ soln. and3× extracted with TBME. The combined org. phases were washed with brine,dried over Na₂SO₄, filtered and concentrated to leave the title compoundas a colourless solid. HPLC Rt_(H4)=0.68-0.70 min; ESIMS: 352, 354[(M+H)⁺].

h)[(2R,5R)-5-(6-Bromo-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester and (2R,5S)-diastereomer

A mixture of(R)-5-(6-Bromo-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine,Boc₂O and DIPEA in DCM (4 ml) was stirred at rt for 20 h. The reactionmixture was quenched with sat. aq. NaHCO₃ soln. and diluted with DCM.The phases were separated and the aq. phase was twice reextracted withDCM. The combined org. phases were washed with brine, dried over Na₂SO₄,filtered and concentrated. HPLC purification (Alltech Grom Saphir 65 Si,10 μm, 250×50 mm column, gradient Hept:EtOAc 0-1.6 min 85:15, 1.6-16 min0:100, 16-21.2 min 0:100, flow: 100 ml/min, detection: 254 nm) yieldedthe desired (2R,5R) as well as the undesired (2R,5S) diastereomer. HPLCRt_(H4)=1.28 min (2R, 5S), 1.30 min (2R, 5R); ESIMS: 452, 454 [(M+H)⁺];¹H NMR (2R, 5R) (400 MHz, CDCl₃): δ 10.98 (br s, 1H), 7.59 (t, 1H), 7.43(d, 1H), 7.34 (d, 1H), 4.39 (d, 1H), 4.08 (d, 1H), 1.62 (s, 3H), 1.55(s, 12H); 1H NMR (2R, 5S) (400 MHz, CDCl₃): δ 11.01 (br s, 1H), 7.57 (t,1H), 7.42 (d, 1H), 7.37 (d, 1H), 4.45 (d, 1H), 3.91 (d, 1H), 1.74 (s,3H), 1.65 (s, 3H), 1.55 (s, 19H).

i)((2R,5R)-5-{6-[(5-Cyano-3-methyl-pyridine-2-carbonyl)-amino]-pyridin-2-yl}-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester

A mixture of[(2R,5R)-5-(6-Bromo-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (60.00 mg, 0.133 mmol),5-cyano-3-methylpicolinamide (23.52 mg, 0.146 mmol), Xantphos (6.91 mg,0.012 mmol) and Cs₂CO₃ (60.50 mg, 0.186 mmol) in dioxane (0.611 ml) wasdegassed with argon for 5 min, then Pd₂dba₃ (3.64 mg, 3.98 μmol) wasadded and the reaction mixture was stirred at 40° C. for 18 h. Thereaction mixture was diluted with H₂O and TBME. The phases wereseparated and the aq. phase was reextracted with TBME. The combined org.phases were washed with brine, dried over Na₂SO₄, filtered andconcentrated. HPLC purification (Alltech Grom Saphir 65 Si 10 μM column,150×30 mm, gradient n-heptane:EtOAc 0-1.2 min 75:25, 1.2-9 min 0:100,9-12 min 0:100, flow: 50 ml/min, detection: 254 nm) yielded the titlecompound as a colourless solid. HPLC Rt_(H4)=1.37 min; ESIMS: 533[(M+H)⁺]; ¹H NMR (400 MHz, CDCl₃): δ 11.22 (s, 1H), 10.47 (s, 1H), 8.78(d, 1H), 8.33 (d, 1H), 7.98 (d, 1H), 7.84-7.80 (m, 1H), 7.13 (d, 1H),4.37 (d, 1H), 4.11 (d, 1H), 2.88 (s, 3H), 1.64 (s, 3H), 1.57 (br s,12H).

j) 5-Cyano-3-methyl-pyridine-2-carboxylic acid[6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoro-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide

To a solution of((2R,5R)-5-{6-[(5-cyano-3-methyl-pyridine-2-carbonyl)-amino]-pyridin-2-yl}-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester (50.0 mg, 0.094 mmol) in DCM (0.3 ml) was addedTFA (0.289 ml, 428.0 mg, 3.760 mmol) and the reaction mixture wasstirred at rt for 2 h. The solvent was evaporated off, sat. aq. NaHCO₃soln. and TBME was added, the phases were separated and the aq. phasewas reextracted twice with TBME. The combined org. phases were driedover Na₂SO₄, filtered and concentrated and the residue was washed withMeOH to leave the title compound as a colourless crystalline solid. HPLCRt_(H4)=0.84 min; ESIMS: 433 [(M H)⁺]; ¹H NMR (400 MHz, CD₃OD): δ 8.85(s, 1H), 8.21-8.18 (m, 2H), 7.82-7.78 (m, 1H), 7.23 (d, 1H), 4.18 (d,1H), 3.80 (d, 1H), 2.76 (s, 3H), 1.46-1.45 (2s, 6H).

Examples 9 and 10

The compounds listed in Table 5 can be prepared by a procedure analogousto that used in Example 8.

Hydrochloride salts were obtained from solutions of the correspondingfree base by addition of hydrochloric acid in dioxane or hydrochloricacid in diethylether and evaporation of the solvents.

TABLE 5 MS [m/z; Example Compound ¹H-NMR (M + 1)⁺]  9

  5-Cyano-pyridine-2-carboxylic acid [6-((3S,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide hydrochloride (δ; CDCl₃): 10.26(br s, 1H), 8.97 (br s, 1H), 8.45 (d, 1H), 8.29-8.12 (m, 2H), 7.78-7.76(m, 1H), 7.38 (d, 1H), 4.14 (d, 1H), 3.94 (d, 1H), 1.69 (br s, 3H), 1.55(br s, 3H). UPLCMS: Rt_(H4) = 0.77 [M + 1] = 419.3 10

  5-Cyano-pyridine-2-carboxylic acid [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide (δ; CD₃OD): 9.07 (d, 1H),8.45-8.39 (m, 2H), 8.22 (d, 1H), 7.83 (t, 1H), 7.27 (d, 1H), 4.19 (d,1H), 3.83 (d, 1H), 1.47 (s, 6H). UPLCMS: Rt_(H4) = 0.79 [M + 1] = 419.3

Example 11: 5-Cyano-3-methyl-pyridine-2-carboxylic acid[6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide

a) 2-(6-Bromo-3-fluoro-pyridin-2-yl)-propan-2-ol

To a solution of 2-bromo-5-fluoropyridine (25 g, 142 mmol) indiethylether (600 ml) was slowly added n-butyllithium (2.5 M in hexane,56.8 ml, 142 mmol) at −78° C. under a nitrogen atmosphere. The resultingyellow reaction mixture was stirred at −78° C. for 2 hours and dryacetone (11.47 ml, 156 mmol) was added over 30 minutes. Stirring wascontinued at −78° C. for 1 hour. HCl (2N, 50 ml) was added and thereaction mixture was warmed to 0° C. The pH of the mixture was adjustedto ˜7 with 2N HCl solution. The reaction mixture was diluted with ethylacetate and washed with brine, dried over sodium sulfate, filtered andconcentrated in vacuo. The crude product (29.36 g) was chromatographedover silica gel (cyclohexane: ethyl acetate 9:1): 22.3 g (67.1% yield).TLC (cyclohexane/ethyl acetate 9:1) R_(f)=0.33; LCMS Rt_(H5)=0.89 min(ES+ 234, 236). ¹H-NMR (360 MHz, DMSO-d₆): 7.72-7.62 (m, 2H), 5.27 (s,1H, OH), 1.50 (s, 6H, 2×CH₃).

b) 6-Bromo-3-fluoro-2-isopropenyl-pyridine

To a solution of 2-(6-bromo-3-fluoro-pyridin-2-yl)-propan-2-ol (22.3 g,95 mmol) and methanesulfonic acid anhydride (49.8 g, 286 mmol) indichloromethane was added dropwise triethylamine (53.1 ml, 381 mmol) at0° C. The reaction mixture was stirred at room temperature for 20 hours.The reaction mixture was quenched with aq. sodium carbonate solution anddiluted with dichloromethane. The aqueous phase was extracted withdichloromethane. The combined organic layers were washed with brine,dried over sodium sulfate, filtered and evaporated in vacuo (volatile).The crude brown oil was chromatographed over silica (cyclohexane:ethylacetate 9:1) to give the title compound as a clear liquid. 17.35 g (84%yield). TLC (cyclohexane/ethyl acetate 9:1) R_(f)=0.58; ¹H-NMR (360 MHz,CDCl₃): 7.26-7.15 (m, 2H), 5.72 (s, 1H), 5.47 (s, 1H), 2.12 (s, 3H,CH₃).

c) 2-(6-Bromo-3-fluoro-pyridin-2-yl)-propane-1,2-diol

To a solution of 6-bromo-3-fluoro-2-isopropenyl-pyridine (17.35 g, 80mmol) in acetone (45 ml) and water (90 ml) was addedN-methylmorpholine-N-oxide hydrate (11.4 g, 84 mmol) and osmiumtetroxide (5.04 ml, 0.402 mmol). The resulting reaction mixture wasstirred at room temperature for 44 hours. Sodium dithionite (2 g) inwater (70 ml) was added and the reaction mixture was stirred for 15minutes and was then filtered and concentrated in vacuo. Ethyl acetatewas added and the organic layer was washed with brine, dried over sodiumsulfate, filtered and evaporated. 18.29 g slightly yellow solid (91%yield). LCMS Rt_(H5)=0.64 min (ES+250, 252); ¹H-NMR (360 MHz, CDCl₃):7.46 (dd, 1H), 7.35 (dd, 1H), 5.09 (s, 1H, OH), 3.96 (d, 1H), 3.78 (d,1H), 2.45 (broad, 1H, OH), 1.53 (s, 3H, CH₃).

d) Methanesulfonic acid2-(6-bromo-3-fluoro-pyridin-2-yl)-2-hydroxy-propyl ester

To a solution of 2-(6-bromo-3-fluoro-pyridin-2-yl)-propane-1,2-diol(18.29 g, 73.1 mmol) in dichloromethane (350 ml) was added triethylamine(20.39 ml, 146 mmol). Methanesulfonyl chloride (6.27 ml, 80 mmol) wasadded dropwise at 0° C. over 10 minutes. Stirring was continued at 0° C.for 30 minutes. The reaction mixture was washed with sat. sodiumbicarbonate solution, water and brine. The organic layer was dried oversodium sulfate, filtered and evaporated. 31.46 g (crude, used withoutfurther purification in the next step).

LCMS Rt_(H5)=0.81 min. (ES+328, 330); ¹H-NMR (360 MHz, CDCl₃): 7.52 (dd,1H), 7.41 (dd, 1H), 5.13 (s, 1H, OH), 4.61 (d, 1H), 4.45 (d, 1H), 3.05(s, 3H, CH₃SO₂), 1.61 (s, 3H, CH₃).

e) 1-Azido-2-(6-bromo-3-fluoro-pyridin-2-yl)-propan-2-ol

A mixture of methanesulfonic acid2-(6-bromo-3-fluoro-pyridin-2-yl)-2-hydroxy-propyl ester (5 g, 15.24mmol), ammonium chloride (4.08 g, 76 mmol) and sodium azide (2.476 g,38.1 mmol) in ethanol (100 ml) was stirred at 80° C. for 20 hours. Thereaction mixture was diluted with ethyl acetate and washed with waterand brine. The organic layer was dried over sodium sulfate, filtered andevaporated. 3.1 g (74% yield). TLC (cyclohexane/ethyl acetate 9:1)R_(f)=0.35; LCMS Rt_(H5)=0.97 min. (ES+275, 277); ¹H-NMR (360 MHz,CDCl₃): 7.51 (dd, 1H), 7.36 (dd, 1H), 5.18 (s broad, 1H, OH), 3.68-3.60(AB system, 2H), 1.59 (s, 3H, CH₃).

f) 6-Bromo-3-fluoro-2-(2-methyl-aziridin-2-yl)-pyridine

To a solution of 1-azido-2-(6-bromo-3-fluoro-pyridin-2-yl)-propan-2-ol(11.2 g, 40.7 mmol) in THF (60 ml) was added triphenylphosphine (10.68g, 40.7 mmol) and the reaction mixture was stirred for 18 hours at roomtemperature. The solvent was removed in vacuo and the residue obtainedwas dissolved in diethylether and filtered through a cotton plug toremove triphenylphosphine oxide. The filtrate was washed with citricacid (9.6 g in 20 ml of water) and the organic phase was separated. Theaqueous layer was made basic with 2N NaOH and extracted withdiethylether. The organic layer was dried over sodium sulfate, filteredand evaporated to yield the title compound with some TPPO present: 8.1 gyellow oil (69% yield). TLC (cyclohexane/ethyl acetate 2:1) R_(f)=0.28;LCMS Rt_(H6)=0.46 (ES+231, 233);

¹H-NMR (400 MHz, CDCl₃): 7.34 (dd, 1H), 7.24 (dd, 1H), 1.99 (s, 1H),1.89 (s, 1H), 1.65 (s, 3H, CH₃).

g)6-Bromo-3-fluoro-2-[2-methyl-1-(2-nitro-benzenesulfonyl)-aziridin-2-yl]-pyridine

To a solution of 6-bromo-3-fluoro-2-(2-methyl-aziridin-2-yl)-pyridine (8g, 27.7 mmol) in THF (48 ml) and water (16 ml) was addedN-methylmorpholine (3.5 ml, 27.7 mmol) and o-nosylchloride. The reactionmixture was stirred for 4 hours at room temperature. 3 g neutral Aloxwas added and the reaction mixture was filtered. The filtrate wasdiluted with dichloromethane, washed with sat. sodium hydrogencarbonatesolution and water. The organic phase was dried over sodium sulfate,filtered and evaporated. 11.2 g of the crude product was purified oversilica gel (cyclohexane:ethyl acetate 60:40) to afford the titlecompound. 8.69 g (75% yield). LCMS Rt_(H5)=1.09 min. (ES+416, 418).¹H-NMR (400 MHz, CDCl₃): 8.27 (m, 1H), 7.80-7.73 (m, 3H), 7.46 (dd, 1H),7.34 (dd, 1H), 3.32 (s, 1H), 3.20 (s, 1H), 2.10 (s, 3H, CH₃).

h)(R)-2-[2-(6-Bromo-3-fluoro-pyridin-2-yl)-2-(2-nitro-benzenesulfonylamino)-propoxy]3,3,3-trifluoro-2-methyl-propionicacid ethyl ester

To a solution of (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acidethyl ester (715 mg, 3.84 mmol) in DMF (4 ml) was added NaH (55%) (154mg, 3.84 mmol) at room temperature and the reaction mixture was stirredfor 30 minutes at room temperature. A solution of6-bromo-3-fluoro-2-[2-methyl-1-(2-nitro-benzenesulfonyl)-aziridin-2-yl]-pyridine(800 mg, 1.922 mmol) in DMF (9 ml) was added and the reaction mixturewas stirred at room temperature for 48 hours. The reaction mixture waspoured onto a mixture of ice/2N HCl/t-butyl-methylether. The organiclayer was washed with sat. sodium bicarbonate solution and brine, driedover sodium sulfate, filtered and evaporated. Silica gel chromatography(cyclohexane/ethyl acetate) afforded the title compound as a mixture of2 diastereoisomers. 300 mg (26% yield). TLC (cyclohexane/ethyl acetate2:1) R_(f)=0.42; LCMS Rt_(H5)=1.25 min (100%, TIC ES+602, 604).

i)(R)-2-[2-(6-Bromo-3-fluoro-pyridin-2-yl)-2-(2-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionamide

A solution of(R)-2-[2-(6-bromo-3-fluoro-pyridin-2-yl)-2-(2-nitro-benzenesulfonylamino)-propoxy]3,3,3-trifluoro-2-methyl-propionicacid ethyl ester (720 mg, 1.195 mmol) in NH3 7N in methanol (19 ml, 133mmol) was stirred at 50° C. for 2 days in a sealed 25 ml microwave vial.The solvent was removed in vacuo and the residue (987 mg) waschromatographed over silica gel (cyclohexane/ethyl acetate) affordingthe title compound as a mixture of two diastereoisomers (500 mg, 73%yield). TLC (cyclohexane/ethyl acetate 1:1) R_(f)=0.30; LC-MSRt_(H5)=1.05 min (ES+573, 575).

j)N-[1-(6-Bromo-3-fluoro-pyridin-2-yl)-2-((R)-1-cyano-2,2,2-trifluoro-1-methyl-ethoxy)-1-methyl-ethyl]-2-nitro-benzenesulfonamide

To a solution of(R)-2-[2-(6-bromo-3-fluoro-pyridin-2-yl)-2-(2-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionamide(200 mg, 0.349 mmol) and triethylamine (0.121 ml, 0.872 mmol) indichloromethane (3 ml) was added TFAA (0.059 ml, 0.419 mmol) at 0-5° C.and the reaction mixture was stirred for 18 hours at room temperature.Further addition of TFFA and triethylamine (0.6 and 1.2 equivalent,respectively) brought the reaction to completion after 24 hours. Thereaction mixture was added to a cold sat. sodium bicarbonate solutionand the product was extracted with dichloromethane. The organic layerwas washed with cold 0.1 N HCl solution, water and sat. sodiumbicarbonate solution, dried over sodium sulfate, filtered and evaporatedin vacuo. 190 mg (98% yield) crude product as a mixture of 2diastereoisomers. TLC (cyclohexane/ethyl acetate 3:1) R_(f)=0.24; LCMSRt_(H5)=1.20 min (ESI+ 555, 557).

k)(2R,5S)-5-(6-Bromo-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamineand(2R,5R)-5-(6-Bromo-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine

A solution ofN-[1-(6-bromo-3-fluoro-pyridin-2-yl)-2-((R)-1-cyano-2,2,2-trifluoro-1-methyl-ethoxy)-1-methyl-ethyl]-2-nitro-benzenesulfonamide(1000 mg, 1.801 mmol), potassium carbonate (548 mg, 3.96 mmol) andN-acetylcysteine (588 mg, 3.6 mmol) in ethanol (17 ml) was stirred at80° C. for 3 days until all starting material was consumed. The reactionmixture was concentrated in vacuo and the yellow foam redissolved inethyl acetate and 20% aqueous potassium carbonate solution. The organicphase was washed with sat. sodium bicarbonate solution and brine, driedover magnesium sulfate, filtered and evaporated. 660 mg yellow oil. The2 diastereoisomers were separated via normal phase preparative HPLCchromatography (cychlohexane/ethyl acete/MeOH).

(2R,5S)-5-(6-Bromo-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine(Cis Derivative)

76 mg. TLC (toluene/ethyl acetate 8:2+5% ETA) R_(f)=0.26; LCMSRt_(H4)=0.73 min (100% purity, EI+ 370, 372); 1H-NMR (600 MHz, DMSO-D₆):7.69-7.61 (m, 2H), 6.0 (broad s, 2H, NH2, amidine), 4.15 (d, 1H,AB-system), 3.71 (s, 1H, AB-system), 1.59 (s, 3H, CH₃), 1.47 (s, 3H,CH₃).

(2R,5R)-5-(6-Bromo-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine(Trans Derivative)

89 mg. TLC (toluene/ethyl acetate 8:2+5% ETA) R_(f)=0.31; LCMSRt_(H4)=0.73 min (100% purity, EI+ 370, 372); 1H-NMR (600 MHz, DMSO-D₆):7.73-7.61 (m, 2H), 6.0 (broad s, 2H, NH2, amidine), 4.04 (d, 1H,AB-system), 3.72 (d, 1H, AB-system), 1.52 (s, 3H, CH₃), 1.48 (s, 3H,CH₃).

l) 5-Cyano-3-methyl-pyridine-2-carboxylic acid[6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide

A mixture of(2R,5R)-5-(6-bromo-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine(80 mg, 0.216 mmol), 5-cyano-3-methyl-pyridine-2-carboxylic acid amide(34.8 mg, 0.216 mmol, see Intermediates Amide 1), xantphos (11.26 mg,0.019 mmol) and cesium carbonate (99 mg, 0.303 mmol) in dioxane (2 ml)was degassed for 5 minutes with argon. Pd₂(dba)₃ (5.94 mg, 6.48 μmol)was added, the microwave vial was sealed and stirred at 80° C. for 18hours. The reaction mixture was diluted with water and TBME. The organicphase was washed with brine, dried over sodium sulfate, filtered andevaporated. 173 mg orange solid. Silica gel chromatography (applied ontwo 20×20 cm plate, 1 mm, dichloromethane:methanol 9:1,rechromatographed with dichloromethane:methanol 95:5 with doubleevolution of the plates) afforded the titel compound: 15 mg and 21 mg.Combined amount: 36 mg (37% yield). TLC (dichloromethane/methanol 9:1)R_(f)=0.53; API ES+MS 451. LCMS Rt_(H4)=0.87 min. (100%, ES+451), ¹H-NMR(400 MHz, CDCl₃): 10.80 (br s, 1H), 8.83 (br s, 1H), 8.41 (dd, 1H), 7.93(br s, 1H), 7.55 (t, 1H), 5.8-4.6 (very broad, 2H), 4.23 (br s, 2H),2.83 (s, 3H), 1.75 (s, 3H), 1.66 (s, 3H).

Example 12: 5-Cyano-3-methyl-pyridine-2-carboxylic acid[6-((3S,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide

5-Cyano-3-methyl-pyridine-2-carboxylic acid[6-((3S,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amidecan be prepared by a procedure analogous to that used in Example 11.

TLC (dichloromethane/methanol 9:1) R_(f)=0.47; API ES+MS 451. LCMSRt_(H4)=0.86 min. (100%, ES+451); ¹H-NMR (400 MHz, CDCl₃): 10.65 (br s,1H), 8.83 (d, 1H), 8.37 (dd, 1H), 7.96 (d, 1H), 7.51 (dd, 1H), 6.0-5.0(very broad, 2H), 4.38 (d, 1H), 4.09 (d, 1H), 2.85 (s, 3H), 1.78 (s,3H), 1.71 (s, 3H).

Example 13:5-{2-[(5-Chloro-4,6-dideutero-3-trideuteromethyl-pyridine-2-carbonyl)-amino]-pyridin-4-yl}-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl-ammoniumacetate

a) 2-(2-Bromo-pyridin-4-yl)-malonic acid diethyl ester

2-Bromo-4-methyl pyridine (70.0 g, 407 mmol) was added drop wise to acooled (−78° C.) solution of LDA (2.0 M in toluene/THF/ethyl benzene,610.4 ml, 1.22 mol) in dry THF (600 ml) for 30 min. ethylchloroformate(132.3 g, 1.22 mol) was added to the resultant reaction mixture withaddition funnel at −78° C. and stirring continued for 90 min. Reactionmixture was treated with saturated NH₄Cl solution and worked up withethyl acetate by washing with water, brine followed by drying over anhy.Na₂SO₄. Organic layer was concentrated under reduced pressure to obtaincrude product which was purified by column chromatography with 10% ethylacetate in Hexane to furnish title compound as a brown color oilyliquid. Yield: 115.0 g (89%). TLC (10% ethyl acetate in hexane)R_(f)=0.15; LCMS: Rt_(H8)=1.475 [M+1]⁺=315.8 and 317.8; HPLCRt_(H9)=7.30 min (86.7%); ¹H NMR (400 MHz, CDCl₃) δ 8.38 (d, 1H), 7.56(t, 1H), 7.34 (dd, 1H), 4.55 (s, 1H), 4.29-4.18 (m, 4H), 1.28 (t, 6H).

b) (2-Bromo-pyridin-4-yl)-acetic acid

A suspension of 2-(2-bromo-pyridin-4-yl)-malonic acid diethyl ester (115g, 316 mmol) and K₂CO₃ (125.23 g, 907.5 mmol) in water (500 ml) washeated at 100° C. for 8 h under constant stirring. Reaction mixture wascooled to rt and concentrated under reduced pressure to remove solventcompletely. The solid residue was dissolved in minimum quantity of water(25 ml) and washed with 20% ethyl acetate in hexane to remove non polarimpurities. The aqueous layer was separated and cooled to 0° C. followedby adjusting pH 6 to 7 using aq. 6 N HCl. The precipitated solid wasfiltered using Buchner funnel, washed with ice cold water and driedunder vacuum to furnish title compound as an off white solid. withsufficient purity. Yield: 60.0 g (76.3%). TLC (70% ethyl acetate inhexane) R_(f)=0.05;

LCMS: Rt_(H8)=0.193; [M+1]⁺=215.9 and 217.9; HPLC Rt_(H9)=3.025 min(98%); ¹H NMR (400 MHz, CDCl₃): δ 12.71 (s, 1H), 8.33 (d, 1H), 7.61 (s,1H), 7.37 (d, 1H), 3.71 (s, 3H).

c) (2-Bromo-pyridin-4-yl)-acetic acid ethyl ester

To a solution of (2-bromo-pyridin-4-yl)-acetic acid (60.0 g, 277.7 mmol)in ethanol (600 ml), conc: sulfuric acid (5.0 ml) was added at rt andthe reaction mixture was heated at 90° C. for 9 h. Reaction mixture wascooled to rt and concentrated under reduced pressure to remove solventcompletely. The residue obtained was cooled to 0° C. and pH was adjustedto 8 using 10% aqueous NaHCO₃ solution. The resultant contents wereworked up with ethyl acetate by washing with water, brine and dried overanhy. Na₂SO₄. Organic layer was concentrated under reduced pressure toobtain crude compound. Column chromtography purification of the crudecompound using 15% ethyl acetate in hexane as eluent furnished titlecompound as a brown oil. Yield: 65.0 g (88.5%). TLC (30% ethyl acetatein hexane) R_(f)=0.39; LCMS: Rt_(H7)=0.824 [M+1]⁺=243.8 and 245.8; HPLCRt_(H9)=3.759 min (69%); ¹H NMR (300 MHz, CDCl₃): δ 8.32 (t, 1H), 7.43(s, 1H), 7.21-7.15 (M, 1H), 4.18 (q, 2H), 1.27 (t, 3H).

d) 2-(2-Bromo-pyridin-4-yl)-3-hydroxy-2-hydroxymethyl-propionic acidethyl ester

To an ice cooled stirred mixture of (2-bromo-pyridin-4-yl)-acetic acidethyl ester (40.0 g, 163.93 mmol) and paraformaldehyde (9.84 g, 327.8mmol) in dry DCM was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.49 g,1.49 ml, 9.83 mmol) and stirred for 2 h. Reaction mixture was treatedwith (1R)-(−)-10-camphor sulphonic acid (2.283 g, 9.83 mmol) at 0° C.and the organic layer was washed with brine and dried over anhydrousNa₂SO₄. Concentration of organic layer afforded gummy oily material. Thecrude compound was purified over triethyl amine treated silicagel using5-8% methanol in DCM as eluent furnished title compound as a brownliquid. Yield=20.0 g (40%). TLC (30% ethyl acetate in hexane)R_(f)=0.06; LCMS: Rt_(H7)=0.191; [M+1]⁺=303.9 and 305.8; HPLCRt_(H9)=6.019 min (43%); ¹H NMR (400 MHz, CDCl₃): δ 8.36-8.31 (m, 1H),7.34-7.25 (m, 1H), 6.37-6.33 (m, 1H), 4.6 (d, 1H), 4.14-4.08 (m, 2H),4.04-3.91 (m, 4H), 1.13 (t, 3H).

e) 5-(2-Bromo-pyridin-4-yl)-2,2-dimethyl-[1,3]dioxane-5-carboxylic acidethyl ester

A mixture of2-(2-bromo-pyridin-4-yl)-3-hydroxy-2-hydroxymethyl-propionic acid ethylester (30.0 g, 98.6 mmol) 2,2-dimethoxy propane (51.11 g, [60.5 ml],493.1 mmol) and (1R)-(−)-10-camphor sulphonic acid (5.72 g, 24.65 mmol)in DMF (100 ml) was heated at 80° C. for 10 h. Reaction mixture wascooled to rt and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate and worked up by washing with water, brine,followed by drying over anhy. Na₂SO₄. Organic layer was concentratedunder reduced pressure and the crude product was purified by columnchromatography using 10% ethyl acetate in Hexane to obtain titlecompound as a yellow solid. Yield=18.15 g (53%). TLC (30% ethyl acetatein hexane) R_(f)=0.52; LCMS: Rt_(H7)=1.487; [M+1]⁺=344.0 and 346.0; HPLCRt_(H9)=7.6 min (74%); ¹H NMR (300 MHz, CDCl₃): δ 8.41-8.34 (t, 1H),7.54 (s, 1H), 7.32-7.28 (m, 1H), 4.51 (dd, 2H), 4.27-4.21 (q, 4H), 1.45(s, 3H), 1.39 (s, 3H), 1.23 (t, 3H).

f) 5-(2-Bromo-pyridin-4-yl)-2,2-dimethyl-[1,3]dioxane-5-carboxylic acidethyl ester

A solution of LiOH.H₂O (11.1 g, 263.5 mmol) in water (10 ml) was addedto a solution of5-(2-bromo-pyridin-4-yl)-2,2-dimethyl-[1,3]dioxane-5-carboxylic acidethyl ester (18.1 g, 52.7 mmol) in ethanol (60 ml) at 0° C. and theresultant reaction mixture was stirred at rt for 3 h. Reaction mixturewas concentrated under reduced pressure to remove solvent completely.The wet mass obtained was cooled to 0° C., acidified with glacial aceticacid (to maintain pH ˜6) and the product was extracted with ethylacetate (2×100 ml). Organic layer was washed with brine and concentratedto afford brown solid which was used in the next step without furtherpurification. Yield=14.1 g (85%). TLC (50% ethyl acetate in hexane)R_(f)=0.03;

LCMS: Rt_(H8)=0.343 [M+1]⁺=316.0, 318.0; ¹H NMR (300 MHz, CDCl₃): δ8.28-8.21 (t, 1H), 7.7 (s, 1H), 7.58-7.54 (m, 1H), 4.21-3.95 (dd, 4H),1.36 (s, 3H), 1.14 (s, 3H).

g) 5-(2-Bromo-pyridin-4-yl)-2,2-dimethyl-[1,3]dioxan-5-ylamine

Dipheny phosphoryl azide (14.3 mL, 66.45 mmol) was added to a solutionof 5-(2-bromo-pyridin-4-yl)-2,2-dimethyl-[1,3]dioxane-5-carboxylic acidethyl ester (14.0 g, 44.3 mmol) and triethyl amine (17.24 ml, 133.0mmol) in toluene (100 ml) at 0° C. The resultant reaction mixture washeated to 80° C. under constant stirring for 7 h. Reaction mixture wasconcentrated under reduced pressure to remove solvent completely. Theresidue obtained after concentration was dissolved in THF (100 ml) andcooled to 0° C. 2 N aq. NaOH solution was added drop wise and stirredfor 30 min at rt. Reaction mixture was concentrated under reducedpressure to remove THF and the residue obtained was extracted withethylacetate. Organic layer was washed with water, brine and dried overanhy. Na₂SO₄. Organic layer was concentrated under reduced pressure toobtain furnished brownish oily material which was solidified at lowtemperature (<10° C.). Yield=9.5 g (75%). TLC (50% ethyl acetate inhexane) R_(f)=0.15; LCMS: Rt_(H7)=0.083; [M+1]⁺=287.0 and 289.0.

h)N-[5-(2-Bromo-pyridin-4-yl)-2,2-dimethyl-[1,3]dioxan-5-yl]-2-chloro-acetamide

To a solution of5-(2-bromo-pyridin-4-yl)-2,2-dimethyl-[1,3]dioxan-5-ylamine (9.5 g, 33.1mmol) in DCM (100 ml) was added aq. Na₂CO₃ (8.7 g in 50 ml) at 0° C. andstirring continued for 5 min. Chloroacetyl chloride (2.9 ml, 36.41 mmol)was added to the resultant reaction mixture drop wise and stirred for 30min at 0° C. Reaction mass was diluted with DCM (200 ml) and organiclayer was washed successively washed with water, brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to obtain brownsolid. The product was directly used in the next step with furtherpurification. Yield=10.2 g (85%). TLC (50% ethyl acetate in hexane)R_(f)=0.15; LCMS: Rt_(H8)=0.55 [M+1]⁺=363.0 and 364.9.

i)N-[1-(2-Bromo-pyridin-4-yl)-2-hydroxy-1-hydroxymethyl-ethyl]-2-chloro-acetamide

A solution ofN-[5-(2-bromo-pyridin-4-yl)-2,2-dimethyl-[1,3]dioxan-5-yl]-2-chloro-acetamide(10.0 g, 27.6 mmol) in DCM (150 ml) was cooled to 0° C. for 10 min. andtrifluoromethyl acetic acid (15.0 ml) was added. Stirring continued for2 h and the resultant contents were concentrated under reduced pressure.The residue formed was basified with aq. NH₄OH solution and the productwas extracted with ethyl acetate (3×200 ml) by washing organic layerwith brine (5.0 ml) and dried over anhy. Na₂SO₄. Organic layer wasconcentrated under reduced pressure to obtain title compound as a brownliquid which was carried to next step without any purification.Yield=8.1 g (91%). TLC (70% ethyl acetate in hexane) R_(f)=0.15;

LCMS: Rt_(H8)=0.12 [M+1]⁺=322.9 and 324.9; HPLC Rt_(H9)=5.266 min (61%),5.104 (25%).

j) 5-(2-Bromo-pyridin-4-yl)-5-hydroxymethyl-morpholin-3-one

To a solution ofN-[1-(2-bromo-pyridin-4-yl)-2-hydroxy-1-hydroxymethyl-ethyl]-2-chloro-acetamide(8.0 g, 24.8 mmol) in t-BuOH (50 ml) was added t-BuOK (5.5 g, 49.6 mmol)and NaI (0.375 g, 2.48 mmol) and heated to 90° C. for 1 h. Reaction masswas concentrated under reduced pressure and diluted the residue withEtOAc. Organic layer was separated and washed with ammonium chloridesolution, brine followed by drying over anhy. Na₂SO₄. The crude productwas purified by column chromatography using 5% methanol in DCM to obtaintitle compound as a pale brown gum. Yield=3.25 g (46%). TLC (ethylacetate) R_(f)=0.17; LCMS: Rt_(H8)=0.12; [M+1]⁺=286.7 and 289.

k) 5-(2-Bromo-pyridin-4-yl)-5-fluoromethyl-morpholin-3-one

To a suspension of5-(2-bromo-pyridin-4-yl)-5-hydroxymethyl-morpholin-3-one (3.25 g, 11.0mmol), Na₂CO₃ (3.5 g, 13.06 mmol) in dry THF (15 ml) was addeddiethylaminosulfur trifluoride (2.25 ml, 17.0 mmol) at 0° C. Thereaction mixture was allowed to warm to rt and stirred for 2 h. SolidNa₂CO₃ (3.5 g) was again added to the reaction mixture and stirred for 4h at rt. Solids present in the reaction mixture filtered through Buchnerfunnel. Filtrate was concentrated under reduced pressure and the crudeproduct was purified by column chromatography using 5% methanol in DCMto obtain title compound as a pale yellow solid.

Yield=2.1 g (66%). TLC (50% ethyl acetate in hexane) R_(f)=0.17; LCMS:Rt_(H7)=0.201; [M+1]⁺=289 and 291; HPLC: Rt_(H9)=5.171 min. (50%) and5.063 (21%).

l) 5-Chloro-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acid[4-(3-fluoromethyl-5-oxo-morpholin-3-yl)-pyridin-2-yl]-amide

A stirred solution of5-(2-bromo-pyridin-4-yl)-5-fluoromethyl-morpholin-3-one (0.2 g, 0.695mmol), 5-chloro-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylicacid (Acid 2) (0.135 g, 0.763 mmol) and cesium carbonate (0.678 g, 2.085mmol) in 1,4-dioxane (5.0 ml) was degassed with argon for 10 min.4,5-Bis(diphenyl phosphino)-9,9-dimethyl xanthenes (0.041 g, 0.035 mmol)was added to the resultant mixture and degassed again for 10 min.Tris(dibenzylidene-acetone) di palladium(0) (0.032 g, 0.07 mmol) wasthen added finally and degassed with argon for further 5 min. Reactionmixture was heated to 80° C. for 20 h and cooled to rt. Water was addedto the reaction mixture and product was extracted with ethyl acetate bywashing with brine followed by drying over anhy. Na₂SO₄. The organiclayer was concentrated under reduced pressure to obtain title compoundas a sticky solid which was used for the next step without purification.Yield=0.14 g (52%). TLC (50% ethyl acetate in hexane) R_(f)=0.45; LCMS:Rt_(H8)=0.868 [M+1]⁺=384.0; ¹H NMR (300 MHz, CDCl₃): δ 10.7 (s, 1H),8.51-8.41 (m, H) 7.51-7.46 (d, 1H), 7.34-7.16 (m, 1H), 4.99-4.60 (m,2H), 4.34-3.79 (m, 4H).

m) 5-Chloro-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acid[4-(3-fluoromethyl-5-thioxo-morpholin-3-yl)-pyridin-2-yl]-amide

Lawesson's reagent (0.46 g, 1.135 mmol) was added to a stirred solutionof 5-chloro-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acid[4-(3-fluoromethyl-5-oxo-morpholin-3-yl)-pyridin-2-yl]-amide (0.14 g,0.378 mmol) in THF (4.0 ml) and heated to reflux for 2 h. The reactionmixture was concentrated under reduced pressure to obtain crude productas a sticky solid which was purified by column chromatography using 25%ethyl acetate in hexane as eluent to obtain title compound as a stickysolid. Yield=0.095 g (65%). TLC (30% ethyl acetate in hexane)R_(f)=0.61; LCMS: Rt_(H8)=1.489 [M+1]⁺=399.8.

n)5-{2-[(5-Chloro-4,6-dideutero-3-trideuteromethyl-pyridine-2-carbonyl)-amino]-pyridin-4-yl}-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl-ammoniumacetate

A solution of5-chloro-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acid[4-(3-fluoromethyl-5-thioxo-morpholin-3-yl)-pyridin-2-yl]-amide (0.095g, 0.238 mmol) in 10% methanolic ammonia (5.0 ml) was stirred in asealed tube for 16 h at rt. Reaction mixture was concentrated underreduced pressure to obtain semi-solid. Product was purified bypreparative HPLC method to obtain title compound as a semi solid.Conditions for preparative HPLC: Column: Agilent Zorbax XDB C18. Mobilephase: A: 10 mm; ammonium acetate; B: ACN, 60 ml; Flow: 20 ml/min.;Gradient: 0-30, 2-40, 10-80. Yield=28 mg (31%).

LCMS: Rt_(H7)=0.191 [M+1]⁺=383.1; HPLC: Rt_(H9) 3.208 min (97%); ¹H NMR(300 MHz, DMSO-d₆): δ 10.52 (s, 1H), 8.35 (dd, 2H), 7.28 (d, 1H), 6.15(br. s, 1H), 4.51-4.28 (m, 2H), 4.07-3.94 (m, 3H),), 3.69 (d, 2H), 1.89(s, 3H); ¹⁹F NMR (376.1): δ −218.9.

Examples 14 and 15

The compounds listed in Table 6 were prepared by a procedure analogousto those used in Example 13.

TABLE 6 MS ¹H-NMR [m/z; Example Compound (δ; DMSO-d₆) (M + 1)⁺] 14

  5-{2-[(5-Chloro-pyridine-2-carbonyl)-amino]-pyridin-4-yl}-5-fluoromethyl-5,6-dihydro-2H- [1,4]oxazin-3-yl-ammoniumtrifluoro-acetate 10.3 (br. s, 1H), 8.83 (d, 1H, J = 2.0 Hz), 8.45 (s,1H), 8.33 (d, 1H, J = 5.2 Hz), 8.26-8.18 (m, 2H), 7.31 (d, 1H, J = 5.6Hz), 6.07 (brs, 2H), 4.51-4.28 (m, 2H), 4.06-3.93 (m, 4H), 3.7-3.67 (m,2H). LCMS: Rt_(H7) = 0.112 [M + 1]⁺ = 363.9 15

  5-Fluoromethyl-5-{2-[(3-methyl-5-thiocarbamoyl-pyridine-2-carbonyl)-amino]-pyridin-4-yl}-5,6-dihydro-2H-[1,4]oxazin-3-yl-ammonium trifluoro-acetate 8.96 (d, 1H),8.51 (s, 2H), 8.45 (d, 2H), 8.19 (s, 1H), 7.32 (d, 2H), 5.11-4.99 (m,2H), 4.72 (s, 3H), 4.27-4.19 (m, 2H), 4.16-4.08 (m, 2H). LCMS: Rt_(H7) =0.118; [M + 1]⁺ = 403.1

Example 16: 5-Cyano-3-methyl-pyridine-2-carboxylic acid[4-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide

a) 2-(2-Bromo-5-fluoro-pyridin-4-yl)-propan-2-ol

To a solution of 2-bromo-5-fluoro-pyridine (CAS 41404-58-4, 25.0 g, 139mmol) in THF (300 ml) was added dropwise LDA (100 ml of a 2M soln. inTHF/heptane/ethylbenzene, 200 mmol) at −78° C. under a N₂ atmosphere.Stirring was continued for 1 h at −78° C., then acetone (20.44 ml, 16.17g, 278 mmol) was added dropwise and stirring was continued at −78° C.for another 1 h. The reaction mixture was quenched with aq. 1M NH₄Clsoln. and diluted with EtOAc. The phases were separated and the aq.phase was twice reextracted with EtOAc. The combined org. phases werewashed with brine, dried over Na₂SO₄, filtered, concentrated. Flashchromatography on silica gel (gradient cyclohexane:EtOAc 100:0 to 90:10)followed by crystallization from pentane yielded the title compound as acolourless solid. HPLC Rt_(H4)=0.81 min; ESIMS: 234, 236 [(M+H)⁺]; ¹HNMR (400 MHz, DMSO-d₆): δ 8.32 (br s, 1H), 7.71 (d, 1H), 5.57 (s, 1H),4.90 (t, 1H), 3.65-3.57 (m, 1H), 3.53-3.44 (m, 1H), 1.39 (s, 3H).

b) 2-Bromo-5-fluoro-4-isopropenyl-pyridine

To a solution of 2-(2-bromo-5-fluoro-pyridin-4-yl)-propan-2-ol (24.7 g,106 mmol) and methanesulfonic anhydride (55.1 g, 317 mmol) in DCM (250ml) was added triethylamine (58.8 ml, 42.7 g, 422 mmol). The reactionmixture was stirred at rt for 20 h. Another 1 eq. (18 g) ofmethanesulfonic anhydride and 1.2 eq. (17 ml) of triethylamine wereadded and the reaction mixture was stirred an additional 20 h at rt. Thereaction mixture was quenched with 1M aq. Na₂CO₃ sol. and diluted withDCM. The phases were separated and the aq. phase was reextracted twicewith DCM. The combined org. phases were washed with brine, dried overNa₂SO₄, filtered and concentrated. Flash chromatography on silica gel(hexane:EtOAc 8:1) yielded the title compound as a clear colourlessliquid. HPLC Rt_(H4)=1.12 min; ESIMS: 216, 218 [(M+H)⁺]; ¹H NMR (400MHz, CDCl₃): δ 8.20 (d, 1H), 7.40 (d, 1H), 5.48-5.44 (m, 2H), 2.14 (s,3H).

c) 2-(2-Bromo-5-fluoro-pyridin-4-yl)-propane-1,2-diol

To a solution of 2-bromo-5-fluoro-4-isopropenyl-pyridine (17.1 g, 79mmol) in acetone (50 mL) and H₂O (100 mL) was added N-methylmorpholineoxide (10.51 g, 87 mmol) and OsO₄ (4.97 mL, 4.02 g, 0.396 mmol). Thebiphasic mixture was stirred at rt for 17 h. The reaction mixture wasquenched with sodium hydrosulfite (1.516 g, 8.71 mmol) in H₂O (50 ml)and stirred at rt for 20 min. The reaction mixture was filtered throughcelite and the celite pad was washed three times with acetone. Thecombined filtrates were evaporated and the residue was taken up withEtOAc and 1N aq. NaOH soln. The phases were separated and the aq. phasewas reextracted with EtOAc. The combined org. phases were dried overNa₂SO₄, filtered and concentrated to yield the title compound as a lightpurple solid. HPLC Rt_(H4)=0.60 min; ESIMS: 250, 252 [(M+H)⁺]; ¹H NMR(400 MHz, DMSO-d₆): δ 8.32 (d, 1H), 7.71 (d, 1H), 5.57 (s, 1H), 4.89 (t,1H), 3.65-3.57 (m, 1H), 3.53-3.45 (m, 1H), 1.39 (s, 3H).

d) Methanesulfonic acid2-(2-bromo-5-fluoro-pyridin-4-yl)-2-hydroxy-propyl ester

To a suspension of 2-(2-bromo-5-fluoro-pyridin-4-yl)-propane-1,2-diol(17.45 g, 69.8 mmol) and triethylamine (19.45 ml, 14.12 g, 140 mmol) inDCM (350 ml) at 0° C. was added dropwise methanesulfonyl chloride (5.71ml, 8.39 g, 73.3 mmol) over a period of 10 min. The reaction mixture wasstirred at 0° C. for 30 min, then quenched with 1M aq. NaHCO₃ soln. Thephases were separated, the aq. phase was twice reextracted with DCM andthe combined org. phases were washed with brine, dried over Na₂SO₄,filtered and concentrated. Flash chromatography on silica gel (gradientheptane: EtOAc 0-5 min 88:12, 5-37.5 min 24:76) yielded the titlecompound as a clear oil. HPLC Rt_(H4)=0.76 min; ESIMS: 328, 330[(M+H)⁺]; ¹H NMR (400 MHz, DMSO-d₆): δ 8.22 (d, 1H), 7.82 (d, 1H),4.58-4.47 (m, 2H), 3.04 (s, 3H), 3.00 (s, 1H), 1.64 (s, 3H).

e) 1-Azido-2-(2-bromo-5-fluoro-pyridin-4-yl)-propan-2-ol

To a solution of methanesulfonic acid2-(2-bromo-5-fluoro-pyridin-4-yl)-2-hydroxy-propyl ester (10.36 g, 31.6mmol) in ethanol (160 ml) was added NaN₃ (5.13 g, 79.0 mmol) and NH₄Cl(8.44 g, 158.0 mmol). The reaction mixture was stirred at 80° C. for 20h. The reaction mixture was diluted with H₂O and TBME and the phaseswere separated. The aq. phase was twice reextracted with TBME, thecombined org. phases were washed with brine, dried over Na₂SO₄, filteredand concentrated. HPLC Rt_(H4)=0.89 min; ESIMS: 275, 277 [(M+H)⁺]; ¹HNMR (400 MHz, CDCl₃): δ 8.20 (d, 1H), 7.80 (d, 1H), 3.81 (d, 1H), 3.65(d, 1H), 1.61 (s, 3H).

f) Methanesulfonic acid2-azido-1-(2-bromo-5-fluoro-pyridin-4-yl)-1-methyl-ethyl ester

At 0° C., methanesulfonyl chloride (2.04 ml, 3.00 g, 26.20 mmol) wasdropwise added to a solution of1-azido-2-(2-bromo-5-fluoro-pyridin-4-yl)-propan-2-ol (6.00 g, 21.81mmol) and NEt₃ (3.65 ml, 2.65 g, 26.2 mmol) in DCM (200 ml). Thereaction mixture was stirred at 0° C. for 1 h, then for another 1 h at0° C. to rt. The reaction mixture was quenched with 1M aq. NaHCO₃ soln.and diluted with DCM. The phases were separated and the aq. phase wastwice reextracted with DCM. The combined org. phases were dried overNa₂SO₄, filtered and concentrated. HPLC purification (Alltech GromSaphir 65 Si 10 μM column, 250×50 mm, gradient n-heptane:EtOAc 0-1.6 min85:15, 1.6-16 min 0:100, 16-21.2 min 0:100, flow 100 ml/min, detection254 nm) yielded the title compound as well as recovered startingmaterial that could be reacted again according to the above procedure.HPLC Rt_(H4)=0.96 min; ESIMS: 353, 355 [(M+H)⁺]; ¹H NMR (400 MHz,CDCl₃): δ 8.28 (d, 1H), 7.56 (d, 1H), 4.08 (d, 1H), 3.82 (d, 1H), 3.22(s, 3H), 2.13 (s, 3H).

g)2-Bromo-5-fluoro-4-[2-methyl-1-(2-nitro-benzenesulfonyl)-aziridin-2-yl]-pyridine

A mixture of methanesulfonic acid2-azido-1-(2-bromo-5-fluoro-pyridin-4-yl)-1-methyl-ethyl ester (2.1 g,6.09 mmol) and PPh₃ (1.597 g, 6.09 mmol) in THF (20 mL) was stirred atrt for 30 min. The reaction mixture was evaporated to dryness, theresidue was taken up with TBME and 10% aq. citric acid soln. The aq.phase was reextracted with TBME, the combined org. phases were washedwith H₂O. The combined aq. phases were basified using 2N aq. NaOH soln.and three times extracted with TBME. The combined org. phases were driedover Na₂SO₄, filtered and concentrated to yield2-bromo-5-fluoro-4-(2-methyl-aziridin-2-yl)-pyridine in a mixture withPh₃PO that was used for the next step without further purification,

HPLC Rt_(H4)=0.96 min; ESIMS: 231, 233 [(M+H)⁺].

To a solution of crude2-bromo-5-fluoro-4-(2-methyl-aziridin-2-yl)-pyridine (3.17 g as a 45%mixture with Ph₃PO, 6.17 mmol) and 2-nitrobenzene-1-sulfonyl chloride(1.368 g, 6.17 mmol) in THF (23.15 mL) and H₂O (7.72 mL) was addedN-methylmorpholine and the reaction mixture was stirred at rt for 1.5 h.Alox neutral (2-3 spatula) was added and the reaction mixture wasfiltered through celite, washed with DCM and the filtrates were dilutedwith DCM and 1M aq. NaHCO₃ soln. The phases were separated and the aq.phase was reextracted twice with DCM. The combined org. phases weredried over Na₂SO₄ and concentrated. Flash chromatography on silica gel(heptane:EtOAc 4:1 to 3:1) followed by recrystallization fromEtOAc/hexane yielded the title compound as a colourless solid. HPLCRt_(H4)=1.11 min; ESIMS: 416, 418 [(M+H)⁺]; ¹H NMR (400 MHz, CDCl₃): δ8.31-8.30 (m, 1H), 8.23 (d, 1H), 7.86-7.77 (m, 3H), 7.68 (d, 1H), 3.28(s, 1H), 2.78 (s, 1H), 2.09 (s, 3H).

h)(R)-2-[(RS)-2-(2-Bromo-5-fluoro-pyridin-4-yl)-2-(2-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionicacid ethyl ester

To a solution of2-bromo-5-fluoro-4-[2-methyl-1-(2-nitro-benzenesulfonyl)-aziridin-2-yl]-pyridine(795 mg, 1.91 mmol) and (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionicacid ethyl ester (498 mg, 2.67 mmol) in DMF (8 ml, soln. predried overmol. sieves) was added NaH (99 mg of a 60% dispersion in mineral oil,2.48 mmol) and the reaction mixture was stirred at rt for 3 h. Thereaction mixture was quenched with aq. 1N HCl and diluted with H₂O andTBME. The phases were separated and the aq. phase was twice extractedwith TBME. The combined org. phases were washed with H₂O, dried overNa₂SO₄, filtered and concentrated. Flash chromatography on silica gel(heptane:EtOAc 1:1) yielded the title compound (diastereomer mixture) asa colourless solid. HPLC Rt_(H4)=1.26 min; ESIMS: 602, 604 [(M+H)⁺]; ¹HNMR (400 MHz, CDCl₃): δ 7.99 (m, 1H), 7.95-7.93 (m, 1H), 7.79-7.61 (m,4H), 6.94 (m, 1H), 4.45-4.33 (m, 2H), 3.94-3.81 (m, 2H), 1.85 (m, 3H),1.61 (m, 3H), 1.40-1.34 (m, 3H).

i)(R)-2-[(RS)-2-(2-Bromo-5-fluoro-pyridin-4-yl)-2-(2-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionamide

A solution of(R)-2-[(RS)-2-(2-Bromo-5-fluoro-pyridin-4-yl)-2-(2-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionicacid ethyl ester (920 mg, 1.527 mmol) in 7N NH₃/MeOH (11 ml) was stirredin a sealed glass vial at 55° C. for 44 h. The reaction mixture wasevaporated to dryness to leave a yellow solid that was used for the nextstep without further purification (diastereomer mixture). Rt_(H4)=1.03min; ESIMS: 573, 575 [(M+H)⁺]; ¹H NMR (400 MHz, CDCl₃): δ 8.00 (m, 1H),7.97-7.91 (m, 1H), 7.80-7.63 (m, 3H), 7.55 (m, 1H), 6.63 (m, 1H), 6.41(m, 1H), 5.74 (m, 1H), 4.15 (m, 1H), 3.97 (m, 1H), 1.84 (2s, 3H), 1.69(2s, 3H).

j)N—[(RS)-1-(2-Bromo-5-fluoro-pyridin-4-yl)-2-((R)-1-cyano-2,2,2-trifluoro-1-methyl-ethoxy)-1-methyl-ethyl]-2-nitro-benzenesulfonamide

To a dry solution of(R)-2-[(RS)-2-(2-bromo-5-fluoro-pyridin-4-yl)-2-(2-nitro-benzenesulfonyl-amino)-propoxy]-3,3,3-trifluoro-2-methyl-propionamide(860 mg, 1.35 mmol) in DCM (9 ml) was added at rt NEt₃ (0.470 ml, 342mg, 3.38 mmol). At 0° C., trifluoroacetic anhydride (0.229 ml, 340 mg,1.62 ml) was added dropwise. The reaction mixture was allowed to warm tort and to stir for 1.5 h. The reaction mixture was diluted with 1M aq.Na₂CO₃ soln. and DCM.

The phases were separated and the aq. phase was twice reextracted withDCM. The combined org. phases were dried over Na₂SO₄, filtered andconcentrated to yield the crude title compound as an orange solid thatwas used in the next step without further purification (diastereomermixture). Rt_(H4)=1.19 min; ESIMS: 555, 557 [(M+H)⁺]; ¹H NMR (400 MHz,CDCl₃): δ 8.01-7.93 (m, 2H), 7.79-7.63 (m, 3H), 7.59 (m, 1H), 4.26-4.16(m, 2H), 1.85-1.84 (2d, 3H), 1.78-1.76 (2d, 3H).

k) (2R,5R)- and(2R,5S)-5-(2-Bromo-5-fluoro-pyridin-4-yl)-2,5-dimethyl-2-trifluoro-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine

A mixture ofN-[1-(2-bromo-5-fluoro-pyridin-4-yl)-2-((R)-1-cyano-2,2,2-trifluoro-1-methyl-ethoxy)-1-methyl-ethyl]-2-nitro-benzenesulfonamide(585 mg, 1.053 mmol), N-acetylcysteine (344 mg, 2.107 mmol) and K₂CO₃(291 mg, 2.107 mmol) in EtOH (7 ml) was stirred at 85° C. for 68 h underN₂. The reaction mixture was concentrated to ⅓ of its volume and dilutedwith cold 10% aq. K₂CO₃ soln. and TBME. The phases were separated andthe aq. phase was twice reextracted with TBME. The combined org. phaseswere washed with 1M aq. NaHCO₃ soln. and brine, was dried over Na₂SO₄,filtered and concentrated. HPLC purification (Alltech Grom Saphir 65 Si10 μM column, 150×30 mm, gradient n-heptane:EtOAc:MeOH 0-1.2 min68:30:2, 1.2-9 min 0:80:20, 9-12 min 0:65:35, flow: 50 ml/min,detection: 254 nm) separated the (2R,5R)- from the (2R,5S)-diastereomerof the title compound. Rt_(H4)=0.70 min; ESIMS: 370, 372 [(M+H)⁺]; ¹HNMR (400 MHz, DMSO-d₆):

(2R,5R)-diastereomer δ 8.39 (br s, 1H), 7.81 (d, 1H), 6.28 (br s, 2H),3.94 (d, 1H), 3.75 (d, 1H), 1.49 (s, 3H), 1.41 (s, 3H);

(2R,5S)-diastereomer δ 8.37 (d, 1H), 7.68 (d, 1H), 6.34 (br s, 2H), 3.91(d, 1H), 3.83 (d, 1H), 1.59 (s, 3H), 1.40 (s, 3H).

l) 5-Cyano-3-methyl-pyridine-2-carboxylic acid[4-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide

A mixture of 5-cyano-3-methyl-pyridine-2-carboxylic acid amide (43.5 mg,0.270 mmol),(2R,5R)-5-(2-bromo-5-fluoro-pyridin-4-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]-oxazin-3-ylamine(100.0 mg, 0.270 mmol), Xantphos (14.1 mg, 0.024 mmol) and Cs₂CO₃ (123.0mg, 0.378 mmol) in dioxane (2.5 ml) was degassed with argon for 5 min,then Pd₂(dba)₃ (7.42 mg, 8.11 μmol) was added and the reaction mixturewas stirred at 60° C. for 24 h. The reaction mixture was diluted withH₂O and TBME. The phases were separated and the aq. phase was twicereextracted with TBME. The combined org. phases were washed with brine,dried over Na₂SO₄, filtered and concentrated. Prep HPLC (Alltech GromSaphir 65 Si 10 μM column, 150×30 mm, gradient n-heptane:EtOAc:MeOH0-1.2 min 68:30:2, 1.2-9 min 0:80:20, 9 −12 min 0:65:35, flow: 50ml/min, detection: 254 nm) yielded the parent compound as a colourlesssolid. Rt_(H4)=0.83 min; ESIMS: 451 [(M+H)⁺]; ¹H NMR (400 MHz, DMSO-d₆):δ 10.80 (br s, 1H), 8.98 (br s, 1H), 8.42 (s, 1H), 8.36 (dd, 1H), 8.30(dd, 1H), 6.24 (br s, 2H), 3.97 (d, 1H), 3.82 (d, 1H), 2.58 (s, 3H),1.49 (s, 3H), 1.44 (s, 3H).

The compound in Table 7 can be prepared by a procedure analogous to thatused in Example 16.

TABLE 7 MS ¹H-NMR [m/z; Example Compound (δ; DMSO-d₆) (M + 1)⁺] 17

  5-Cyano-3-methyl-pyridine-2-carboxylic acid [4-((3S,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide 10.75 (s, 1H),8.97 (s, 1H), 8.42 (s, 2H), 8.27 (d, 1H), 6.21 (br s, 2H), 3.91 (s, 2H),2.58 (s, 3H), 1.61 (s, 3H), 1.44 (s, 3H). UPLCMS: Rt_(H4) = 0.79 [M + 1]= 451

Example 18: 5-Bromo-pyridine-2-carboxylic acid[5-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-6-chloro-pyridin-3-yl]-amidehydrochloride

a) 5-Bromo-2-chloro-3-nitromethyl-pyridine

To a solution of 5-bromo-3-bromomethyl-2-chloro-pyridine (4.10 g, 14.37mmol) in TBME (50.3 ml) in a tin-foil wrapped flask was added silvernitrite (2.65 g, 17.24 mmol) and the reaction mixture was stirred atroom temperature for 15 h. The solid was filtered off, rinsed with TBMEand the filtrate was evaporated. The residue was purified bychromatography on silica gel (cyclohexane to cyclohexane/EtOAc 3:2) toprovide the title compound as pale brown oil.

HPLC: Rt_(H4)=0.91 min; ESIMS [M−H]⁻=248.9, 251.0; ¹H-NMR (600 MHz,DMSO-d₆): 8.71 (d, 1H), 8.40 (d, 1H), 5.92 (s, 2H).

b) 2-(5-Bromo-2-chloro-pyridin-3-yl)-2-nitropropane-1,3-diol

To a solution of 5-bromo-2-chloro-3-nitromethyl-pyridine (286 mg, 1.14mmol) in dioxane (2.3 ml) was added 35% aq. formaldehyde (215 mg, 2.50mmol), triethylamine (0.079 ml, 0.57 mmol) and the reaction mixture wasstirred at room temperature for 2 h, to the mixture was added a mixtureof saturated aq. NaCl and 12N HCl (0.05 ml, 0.6 mmol). Then the mixturewas extracted with TBME the combined organic layers were washed withsaturated aq. NaCl, dried with Na₂SO₄ and evaporated. The residue waspurified by chromatography on silica gel (cyclohexane tocyclohexane/EtOAc 1:1) to provide the title compound as colorless solid.M.p. 162-163° C. HPLC: Rt_(H4)=0.69 min; ESIMS [M+H]⁺=311.0, 313.0; ¹HNMR (600 MHz, DMSO-d₆): 8.64 (d, 1H), 8.11 (d, 1H), 5.60 (t, 2H), 4.34(dd, 2H), 4.19 (dd, 2H).

c) 2-(5-Bromo-2-chloro-pyridin-3-yl)-2-nitropropane-1,3-diol

To a suspension of zinc dust (2.03 g, 31 mmol) in acetic acid (8.6 ml)was added dropwise within 1 h a solution of2-(5-bromo-2-chloro-pyridin-3-yl)-2-nitropropane-1,3-diol (1.61 g, 5.17mmol) in acetic acid (17.3 ml) and DMF (5.2 ml), while maintaining thetemperature between 30 and 40° C. (ice cooling), the reaction mixturewas stirred at 40° C. for 1.5 h. The mixture was filtered, the residuerinsed with methanol and at 0° C. the filtrate poured on a 1:1 mixtureof EtOAc and saturated aq. NaHCO₃. The pH was adjusted to 12 by additionof 1N NaOH, the layers separated and the aq. phase extracted with EtOAc.The combined organic layers were washed with saturated aq. NaCl, driedwith Na₂SO₄ and evaporated to provide the title compound as yellowsolid.

HPLC: Rt_(H5)=0.22 min; ESIMS [M+H]⁺=281.0, 283.0; ¹H NMR (400 MHz,DMSO-d₆): 8.43 (d, 1H), 8.38 (d, 1H), 4.80 (t, 2H), 3.93 (dd, 2H), 3.67(dd, 2H), 2.18 (br. s, 2H).

d)N-[1-(5-Bromo-2-chloro-pyridin-3-yl)-2-hydroxy-1-hydroxymethyl-ethyl]-2-chloro-acetamide

To a suspension of2-(5-bromo-2-chloro-pyridin-3-yl)-2-nitropropane-1,3-diol (904 mg, 3.21mmol) in DCM (64 ml) was added pyridine (2.6 ml, 32.1 mmol), aftercooling to −30° C. a solution of chloro-acetylchloride (1.022 ml, 12.84mmol) in DCM (32 ml) was added within 10 min., the reaction mixture wasstirred at −30° C. for 1.5 h. At −30° C. 1M HCl and DCM was added, thelayers were separated, the aq. phase extracted with DCM and the combinedorganic layers washed with half saturated aq. NaHCO₃ and half saturatedaq. NaCl, dried with Na₂SO₄ and evaporated. The obtained per-acetylatedproduct was dissolved in methanol (19.3 ml) and K₂CO₃ powder (222 mg,1.6 mmol) added, the mixture was stirred at room temperature for 30 min.After addition of 1M HCl and TBME the layers were separated, the aq.layer was extracted with TBME, the combined organic layers were washedwith half saturated aq. NaCl, dried with Na₂SO₄ and evaporated. Theresidue was purified by chromatography on silica gel (cyclohexane/EtOAc1:0 to cyclohexane/EtOAc 0:1) to provide the title compound as colorlesssolid.

HPLC: Rt_(H5)=0.51 min; ESIMS [M+H]⁺=356.9, 358.9; ¹H NMR (600 MHz,DMSO-d₆): 8.44 (d, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 5.08 (t, 2H), 4.11(s, 2H), 4.00-3.95 (m, 2H), 3.94-3.89 (m, 2H).

e) 5-(5-Bromo-2-chloro-pyridin-3-yl)-5-hydroxymethyl-morpholin-3-one

To a suspension ofN-[1-(5-bromo-2-chloro-pyridin-3-yl)-2-hydroxy-1-hydroxymethyl-ethyl]-2-chloro-acetamide(622 mg, 1.74 mmol) in tert.-butanol (10.2 ml) was added at 0° C.potassium tert.-butoxide (292 mg, 2.61 mmol), the reaction mixture wasstirred at room temperature for 1 h. Water was added and thetert.-butanol evaporated, the mixture was extracted with EtOAc, thecombined organic layers were washed with half saturated aq. NaCl, driedwith Na₂SO₄ and evaporated to provide the title compound as beige foam.

HPLC: Rt_(H4)=0.58 min; ESIMS [M+H]⁺=320.9, 322.9; ¹H NMR (600 MHz,DMSO-d₆): 8.56 (d, 1H), 8.39 (s, 1H), 8.21 (d, 1H), 5.44 (t, 1H), 4.42(d, 1H), 4.04 (s, 2H), 3.94 (dd, 1H), 3.90 (d, 1H), 3.86 (d, 1H).

f) 5-(5-Bromo-2-chloro-pyridin-3-yl)-5-fluoromethyl-morpholin-3-one

To a suspension of5-(5-bromo-2-chloro-pyridin-3-yl)-5-hydroxymethyl-morpholin-3-one (547mg, 1.70 mmol) in THF (13.6 ml) was added at 0° C. within 5 min asolution of DAST (1.01 ml, 7.65 mmol) in THF (7.2 ml), the reactionmixture was stirred at room temperature for 6 h. The mixture was cooledto 0° C., half saturated aq. Na₂CO₃ was added and the mixture wasextracted with EtOAc, the combined organic layers were washed with halfsaturated aq. NaCl, dried with Na₂SO₄ and evaporated. The residue waspurified by chromatography on silica gel (cyclohexane tocyclohexane/EtOAc 1:4) to provide the title compound as colorless solid.

HPLC: Rt_(H5)=0.66 min; ESIMS [M−H]⁻=320.8, 322.8; ¹H NMR (600 MHz,DMSO-d₆): 8.80 (s, 1H), 8.63 (d, 1H), 8.12 (d, 1H), 5.01-4.93 (m, 1H),4.92-4.85 (m, 1H), 4.37 (dd, 1H), 4.10 (s, 2H), 3.95 (d, 1H).

g)5-[5-(Benzhydrylidene-amino)-2-chloro-pyridin-3-yl)-5-fluoromethyl-morpholin-3-one

To a solution of5-(5-bromo-2-chloro-pyridin-3-yl)-5-fluoromethyl-morpholin-3-one (199mg, 0.615 mmol), benzophenone imine (86 mg, 0.473) and Cs₂CO₃ (620 mg,1.89 mmol) in toluene (4.6 ml) and dioxane (4.6 ml) was added Pd₂(dba)₃(22 mg, 0.024 mmol) and Xantphos (41 mg, 0.071 mmol) and the mixture waspurged with nitrogen, the reaction mixture was heated to 100° C. for 4h. After cooling to 0° C. water was added and the mixture was extractedwith EtOAc, the combined organic layers were washed with water, driedwith Na₂SO₄ and evaporated. The residue was purified by chromatographyon silica gel (cyclohexane to cyclohexane/EtOAc 1:4) to provide thetitle compound as yellowish foam.

HPLC: Rt_(H5)=1.11 min; ESIMS [M+H]⁺=424.1; ¹H NMR (600 MHz, DMSO-d₆):8.71 (s, 1H), 7.80 (s, 1H), 7.70 (d, 2H), 7.58 (t, 1H), 7.50 (t, 2H),7.36 (d, 4H), 7.16 (d, 2H), 4.87-4.70 (m, 2H), 4.28 (d, 1H), 4.04 (d,1H), 3.93 (d, 1H), 3.80 (d, 1H).

h) 5-(5-Amino-2-chloro-pyridin-3-yl)-5-fluoromethyl-morpholine-3-thione

To a solution of5-[5-(benzhydrylidene-amino)-2-chloro-pyridin-3-yl)-5-fluoromethyl-morpholin-3-one(206 mg, 0.467 mmol) in THF (2.4 ml) was added Lawessons's reagent (189mg, 0.467 mmol), the reaction mixture was heated to reflux for 1 h. Thesolvent was evaporated and the crude product dissolved in THF (12 ml),2M HCl (6.3 ml) were added and the mixture stirred at room temperaturefor 17 h. After cooling to 0° C. aq. 2M K₂CO₃ was added and the basicmixture was extracted with EtOAc, the combined organic layers werewashed with half saturated aq. NaCl, dried with Na₂SO₄ and evaporated.The residue was purified by chromatography on silica gel(cyclohexane/EtOAc 1:0 to cyclohexane/EtOAc 0:1) to provide the titlecompound as beige foam.

HPLC: Rt_(H5)=0.59 min; ESIMS [M+H]⁺=276.0; ¹H NMR (600 MHz, DMSO-d₆):10.99 (s, 1H), 7.70 (d, 1H), 7.08 (d, 1H), 5.76 (s, 2H), 4.99 (dd, 1H),4.82 (dd, 1H), 4.46-4.35 (m, 3H), 3.96 (d, 1H).

i) 5-Bromo-pyridine-2-carboxylic acid[6-chloro-5-(3-fluoromethyl-5-thioxo-morpholin-3-yl)-pyridin-3-yl]-amide

A solution of5-(5-amino-2-chloro-pyridin-3-yl)-5-fluoromethyl-morpholine-3-thione (33mg, 0.12 mmol), 5-bromo-pyridine-2-carboxylic acid (36 mg, 0.18 mmol)and HOAt (29 mg, 0.215 mmol) in DMF (0.4 ml) was cooled to 0° C. andDIPEA (0.042 ml, 0.24 mmol) and EDC (34 mg, 0.18 mmol) were added, thereaction mixture was stirred at 0° C. for 10 min, then allowed to warmto room temperature over night. At 0° C. aq. 1M KHCO₃ was added and themixture extracted with toluene. The combined organic layers were washedwith water, dried with Na₂SO₄ and evaporated. The residue was taken upin DCM/MeOH 65/35 from which the product started to crystallize.Filtration, rinsing of the crystallized material with DCM and dryingprovide the title compound as yellow crystals.

TLC (cyclohexane/EtOAc 1:1) R_(f)=0.45; HPLC: Rt_(H5)=1.08 min; ESIMS[M+H]⁺=458.9, 461.0.

j) 5-Bromo-pyridine-2-carboxylic acid[5-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-6-chloro-pyridin-3-yl]-amidehydrochloride

To a suspension of 5-bromo-pyridine-2-carboxylic acid[6-chloro-5-(3-fluoromethyl-5-thioxo-morpholin-3-yl)-pyridin-3-yl]-amide(26 mg, 0.057 mmol) in 7M NH₃ in MeOH (0.23 ml) was added at −20° C.,tert.-butylhydroperoxide (0.055 ml, 0.566 mmol) and aq. 25% NH₃ (0.15ml, 0.99 mmol), the reaction mixture was stirred at room temperature for80 min, 7M NH₃ in MeOH (0.69 ml) were added and stirring continued for20 h. At 0° C. half saturated aq. Na₂S₂O₃ was added and the mixtureextracted with EtOAc. The combined organic layers were washed with halfsaturated aq. NaCl, dried with Na₂SO₄ and evaporated. The residue waspurified by preparative TLC DCM/MeOH 9:1 to yield the desired compoundas colorless foam. The product was dissolved in DCM/MeOH, 5 equivalentsof 5M HCl in Et₂O were added and the solvents evaporated to provide thetitle compound as beige solid.

TLC (DCM/MeOH 9:1) R_(f)=0.22; HPLC: Rt_(H5)=0.71 min; ESIMS[M+H]⁺=442.0, 443.9; ¹H NMR (600 MHz, DMSO-d₆): 11.12 (s, 1H), 8.88 (d,1H), 8.86 (s, 1H), 8.65 (d, 1H), 8.35 (dd, 1H), 8.09 (d, 1H), 6.02 (br.s, 2H), 4.80-4.66 (m, 2H), 4.13-3.93 (m, 4H).

Example 19: 3-Amino-5-cyano-pyridine-2-carboxylic acid[6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide

a)(2R,5R)-5-(6-Amino-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine

To a suspension of(2R,5R)-5-(6-bromo-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine(6.0 g, 17.04 mmol, Example 8 step h), Cu₂O (0.122 g, 0.852 mmol), K₂CO₃(0.471 g, 3.41 mmol) and N,N′-dimethylethylenediamine (0.15 g, 1.704mmol) were suspended in ethylene glycol (34 ml) were added 53 ml aq. NH₃(25% w). The flask was sealed and the suspension was stirred to 60° C.for 20 h. A green solution was obtained. It was occasionally necessaryto shake the flask to make sure that all insoluble parts went insolution. The mixture was partitioned between water and EtOAc. The aq.phase was extracted with EtOAc, the combined org layers were washed withbrine, dried with Na₂SO₄ and evaporated to give 5.11 g of a green resin,which was purified by chromatography on silica gel (DCM/1-4% (EtOH 25%aq NH3 9:1)) to give 2.77 g of the title compound as a colorless foam.

HPLC: Rt_(H2)=2.480 min; ESIMS: 289 [(M+H)⁺]; ¹H-NMR (600 MHz, DMSO-d₆):7.31 (t, 1H), 6.63 (d, 1H), 6.27 (d, 1H), 5.89 (br s, 2H), 5.77 (br s,2H), 3.90 (d, 1H), 3.65 (d, 1H), 1.40 (s, 3H), 1.28 (s, 3H).

b)[(2R,5R)-5-(6-Amino-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

A solution of(2R,5R)-5-(6-amino-pyridin-2-yl)-2,5-dimethyl-2-trifluorormethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine(2.77 g, 9.61 mmol), Boc₂O (2.31 g, 10.57 mmol) and DIPEA (2.2 ml, 12.5mmol) in DCM (28 ml) and THF (2 ml) was stirred for 3 days. The mixturewas evaporated and purified by chromatography on silica gel(hexanes/10-20% EtOAc) to give 3.34 g of the title compound as acolorless solid. HPLC: Rt_(H3)=3.048 min; ESIMS: 389 [(M+H)⁺]; ¹H-NMR(600 MHz, DMSO-d₆): 10.88 (s, 1H), 7.43 (t, 1H), 6.48 (d, 1H), 6.41 (d,1H), 6.01 (br s, 2H), 4.16 (d, 1H), 4.11 (d, 1H), 1.54 (s, 3H), 1.52 (s,3H), 1.45 (s, 9H).

c)((2R,5R)-5-{6-[(3-Amino-5-cyano-pyridine-2-carbonyl)-amino]-pyridin-2-yl}-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester

A mixture of[(2R,5R)-5-(6-amino-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (80 mg, 0.206 mmol),3-amino-5-cyano-pyridine-2-carboxylic acid (40.3 mg, 0.247 mmol, Acid-4,HOAt (50.5 mg, 0.371 mmol) in DMF (1 ml) and EDC.HCl (59.2 mg, 0,309mmol) was stirred overnight. The reaction mixture was diluted withEtOAc, washed with aq. NaHCO₃ and brine, and dried with MgSO₄.H₂O. Thetitle compound was obtained after chromatography on silica gel(toluene/1-3% EtOAc) to give 71 mg of the title compound as a paleyellow solid slightly contaminated with some starting material. HPLC:Rt_(H1)=3.608 min; ESIMS: 534 [(M+H)⁺]; ¹H-NMR (600 MHz, CDCl₃): 10.92(s, 1H), 8.29 (d, 1H), 8.18 (s, 1H), 7.82 (t, 1H), 7.36 (s, 1H), 7.14(d, 1H), 6.33 (br, 1H), 4.39 (d, 1H), 4.12 (d, 1H), 1.66 (s, 3H), 1.60(s, 9H), 1.59 (s, 3H).

d) 3-Amino-5-cyano-pyridine-2-carboxylic acid[6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide

To a solution of((2R,5R)-5-{6-[(3-amino-5-cyano-pyridine-2-carbonyl)-amino]-pyridin-2-yl}-2,5-dimethyl-2-trifluorormethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester (71 mg, 0.133 mmol) in DCM (3 ml) was added TFA (1ml). After stirring for 1.5 h the mixture was poured onto 10% aq. Na₂CO₃and extracted three times with DCM. The combined organic layers weredried with K₂CO₃, filtered and evaporated. The title compound (46 mg)was obtained after chromatography on silica gel (hexanes/15-25%(EtOAc/EtOH 9:1)) as a yellow solid. HPLC: Rt_(H3)=3.027 min; ESIMS: 434[(M+H)⁺]; ¹H-NMR (600 MHz, DMSO-d₆): 10.23 (s, 1H), 8.25 (s, 1H), 8.06(d, 1H), 7.85 (t, 1H), 7.69 (s, 1H), 7.36-7.27 (m, broad, 3H),6.12-6.00, (s, broad, 2H), 3.94 (d, 1H), 3.76 (d, 1H), 1.42 (s, 3H),1.34 (s, 3H).

Examples 20 to 23

The compounds listed in Table 8 can be prepared by a procedure analogousto that used in Example 19.

Hydrochloride salts were obtained from solutions of the correspondingfree base by addition of hydrochloric acid in dioxane or hydrochloricacid in diethylether and evaporation of the solvents.

TABLE 8 MS [m/z; Example Compound ¹H-NMR (M + 1)⁺] 20

  3-Chloro-5-cyano-pyridine-2-carboxylic acid[6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide (δ; DMSO-d₆): 11.04 (brs, 1H), 9.07 (s, 1H), 8.78 (s, 1H), 8.02 (d, 1H), 7.86-7.82 (m, 1H),7.34 (d, 1H), 6.02 (br s, 2H), 3.92 (d, 1H), 3.73 (d, 1H), 1.41 (s, 3H),1.32 (s, 3H) UPLCMS: Rt_(H4) = 0.78 [M + 1] = 453 21

  5-Chloro-4,6-dideuterio-3-trideuteriomethyl-pyridine- 2-carboxylicacid [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide(δ; DMSO-d₆; 600 MHz): 10.41 (s, 1H), 8.08 (d, 1H), 7.83 (t, 1H), 7.30(d, 1H), 6.10- 5.98, (s, broad, 2H), 3.94 (d, 1H), 3.74 (d, 1H), 1.42(s, 3H), 1.33 (s, 3H). LCMS: Rt_(H3) = 3.367 [M + 1] = 447, 449 22

  5-Bromo-3-chloro-pyridine-2-carboxylic acid[6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide (δ; DMSO-d₆; 600 MHz):10.86 (s, 1H), 8.78 (s, 1H), 8.53 (s, 1H), 8.02 (d, 1H), 7.84 (t, 1H),7.28 (d, 1H), 6.10-6.01, (s, broad, 2H), 3.94 (d, 1H), 3.73 (d, 1H),1.41 (s, 3H), 1.32 (s, 3H). LCMS: Rt_(H3) = 3.180 [M + 1] = 506, 508,510 23

  3-Amino-5-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid[6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide (δ;DMSO-d₆; 600 MHz): 9.88 (s, 1H), 8.05-7.72 (s, broad, 2H), 8.03 (d, 1H),7.82 (t, 1H), 7.72 (s, 1H), 7.28 (d, 1H), 6.08- 6.01, (s, broad, 2H),5.03 (q, 2H), 3.92 (d, 1H), 3.74 (d, 1H), 1.41 (s, 3H), 1.33 (s, 3H).LCMS: Rt_(H3) = 3.343 [M + 1] = 508

Example 24: 3-Chloro-5-cyano-pyridine-2-carboxylic acid [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide

a) (2R,5R)-5-(6-Amino-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine and (2R,5S)-5-(6-Amino-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine

A glass/stainless steel autoclave was purged with nitrogen and then amixture of(2R,5S)-5-(6-bromo-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamineand(2R,5R)-5-(6-Bromo-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine(13.3 g, 35.9 mmol, ca. 1:3 mixture, Example 11 (step k) or seealternative procedure below), Cu₂O (1.271 g, 8.88 mmol) and ammonia (150ml, 25%, aq., 1078 mmol, 30 equivalents) in ethylene glycol (215 ml) wasadded. The autoclave was closed and the suspension heated up to 60° C.and the solution was stirred for about 48 hours (max. Pressure 0.9 bar,inside temperature 58-60° C.). The reaction mixture was diluted withethyl acetate and water. The organic phase was washed with water andbrine, dried over sodium sulfate, filtered and evaporated. The darkgreen crude product (13.64 g, containing some ethylen glycol,quantitative yield) was used in the next step without furtherpurification.

LCMS: Rt_(H4)=0.62 min (23%, ES+307) and Rt_(H4)=0.65 min (74%, ES+307)

b) [(2R,5R)-5-(6-Amino-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester and [(2R,5S)-5-(6-Amino-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

A solution of (2R,5R)-5-(6-amino-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine and (2R,5S)-5-(6-Amino-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine(10.99 g, 35.9 mmol, ca. 3:1 mixture), Boc₂O (7.05 g, 32.3 mmol) andHünig's base (7.52 ml, 43.1 mmol) in dichloromethane (120 ml) wasstirred at 0° C. for 4 hours and then at rt over night. The reactionmixture was evaporated and the residue was diluted with ethyl acetate.Crushed ice was added and the mixture was washed with water and brine,dried over sodium sulfate, filtered and evaporated. The crude product(14.23 g) was triturated with toluene/cyclo-hexane/ethyl acetate 4:4:2,cooled and filtered. 5.14 g colorless solid. The filtrate was evaporatedand the resulting mixture was filtered over silica (TBME) to give the 2isomers as an 8:2 mixture (6.31 g). The colorless solid (5.14 g) wasdissolved in dichloromethane and chromatographed over silicagel(toluene/cyclohexane/ethyl acetate 4:4:2) to afford the two isomers.

[(2R,5R)-5-(6-Amino-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

1.38 g, TLC R_(f)=0.16 (toluene:cyclohexane:ethyl acetate 4:4:2), [α]−86.4°, c=0.975 (19.5 mg in 2 ml CHCl₃), LC/MS Rt_(H4)=1.17 min (100%,ES+407/408), HPLC chiral (CHIRACEL oj-h, heptane/ethanol/methanol80:10:10+0.1% dea) Rt=3.937 min (99.16%),% ee 98.3%. ¹H-NMR (400 MHz,CDCl3): 11.50 (s, 1H, NH), 7.24 (t, 1H), 6.47 (br. d, 1H), 4.55-4.40(br. s, 2H, NH2), 4.35 (d, 1H, AB), 4.10 (d, 1H, AB-system), 1.71 (s,3H, CH3), 1.69 (s, 3H, CH3), 1.55 (s, 9H).

[(2R,5S)-5-(6-Amino-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

1.12 g, TLC R_(f)=0.19 (toluene:cyclohexane:ethyl acetate 4:4:2), [α]+72.9°, c=1.01 (20.2 mg in 2 ml CHCl₃), LC/MS Rt_(H4)=1.16 min (100%,ES+407/408), HPLC chiral (CHIRACEL oj-h, heptane/ethanol/methanol80:10:10+0.1% dea) Rt=5.36 min (99.44%),% ee 98.9%. ¹H-NMR (400 MHz,CDCl₃): 11.65 (s, 1H, NH), 7.23 (t, 1H), 6.47 (br. d, 1H), 4.55-4.40(br. s, 2H, NH2), 4.35 (dd, 1H, AB), 4.24 (d, 1H, AB-system), 1.78 (s,3H, CH3), 1.70 (s, 3H, CH3), 1.58 (s, 9H).

Mixed fractions (2.53 g) and recovered material from the filtrate (6.31g) were purified separately affording additional 4.13 g of [(2R,5R)-5-(6-amino-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester and 1.07 g of [(2R,5S)-5-(6-amino-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester.

c) ((2R,5R)-5-{6-[3-Chloro-5-cyano-pyridine-2-carbonyl)-amino]-3-fluoro-pyridin-2-yl}-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester

A mixture of [(2R,5R)-5-(6-amino-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (406 mg, 0.999 mmol), 3-chloro-5-cyanopicolinicacid (201 mg, 1.099 mmol), HOAt (245 mg, 1.798 mmol) and EDChydrochloride (287 mg, 1.499 mmol) was stirred in DMF (10.2 ml) at rtfor 44 hours. The reaction mixture was diluted with toluene and washedwith sat. aq. sodium bicarbonate solution, water and brine, dried oversodium sulfate, filtered and evaporated. The crude product (595 mg) waschromatographed over silicagel (toluene: ethyl acetate 9:1) to yield thetitle compound: 455 mg (76% yield).

TLC (silica, toluene:ethyl acetate 9:1) R_(f)=0.28; ESIMS [M+H]⁺ 571,573;

¹H-NMR (400 MHz, CDCl₃): 11.7 (s, 1H, NH), 10.33 (s, 1H), 8.80 (s, 1H),8.45 (br. d, 1H), 8.24 (s, 1H), 7.60 (br. t, 1H), 4.40 (d, 1H, AB), 4.20(d, 1H, AB), 1.75 (s, 3H), 1.68 (s, 3H), 1.62 (s, 9H).

d) 3-Chloro-5-cyano-pyridine-2-carboxylic acid[6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide

A mixture of ((2R,5R)-5-{6-[3-chloro-5-cyano-pyridine-2-carbonyl)-amino]-3-fluoro-pyridin-2-yl}-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester (450 mg, 0.788 mmol) and TFA (0.90 ml, 11.68 mmol)in dichloromethane (9 ml) was stirred at rt for 5 hours. The solvent wasevaporated and the residue diluted with ethyl acetate and aq. ammonia.Ice was added and the organic phase was washed with water and brine,dried over sodium sulfate, filtered and evaporated. Colorless solid: 360mg (96% yield).

LC-MS: Rt_(H4)=0.79 min (99%, ESI+ 471, 473);

¹H-NMR (400 MHz, CDCl₃): 10.2 (br. s, 1H, NH), 8.85 (d, 1H), 8.35 (dd,1H), 8.20 (d, 1H), 7.50 (dd, 1H), 4.32 (d, 1H, AB), 3.93 (d, 1H, AB),1.64 (s, 3H), 1.54 (s, 3H).

Alternative Stereoselective Procedure for the Preparation of(2R,5R)-5-(6-bromo-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylaminea) 2-Bromo-5-fluoro-4-triethylsilanyl-pyridine

A solution of diisopropylamine (25.3 g, 250 mmol) in 370 ml THF wascooled with a dry-ice acetone bath at −75° C. BuLi (100 ml, 250 mmol,2.5 M in hexanes) was added dropwise while maintaining the temperaturebelow −50° C. After the temperature of the mixture had reached −75° C.again, a solution of 2-bromo-5-fluoropyridine (36.7 g, 208 mmol) in 45ml THF was added dropwise. The mixture was stirred for 1 h at −75° C.Triethylchlorosilane (39.2 g, 260 mmol) was added quickly. Thetemperature stayed below −50° C. The cooling bath was removed and thereaction mixture was allowed to warm to −15° C., poured onto aq. NH₄Cl(10%). TBME was added and the layers were separated. The organic layerwas washed with brine, dried with MgSO₄.H₂O, filtered and evaporated togive a brown liquid which was distilled at 0.5 mm Hg to yield the titlecompound as a slightly yellow liquid (b.p. 105-111° C.). HPLC:Rt_(H11)=2.284 min; ESIMS: 290, 292 [(M+H)⁺, 1Br]; ¹H-NMR (400 MHz,CDCl₃): 8.14 (s, 1H), 7.40 (d, 1H), 1.00-0.82 (m, 15H).

b) 1-(6-Bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-ethanone

A solution of diisopropylamine (25.4 g, 250 mmol) in 500 ml THF wascooled to −75° C. BuLi (100 ml, 250 mmol, 2.5 M in hexanes) was addeddropwise while maintaining the temperature below −50° C. After thereaction temperature had reached −75° C. again, a solution of2-bromo-5-fluoro-4-triethylsilanyl-pyridine (56.04 g, 193 mmol) in 60 mlTHF was added dropwise. The mixture was stirred in a dry ice bath for 70minutes. N,N-dimethylacetamide (21.87 g, 250 mmol) was added quickly,the reaction temperature rose to −57° C. The reaction mixture wasstirred in a dry ice bath for 15 min and then allowed to warm to −40° C.It was poured on a mixture of 2M aq. HCl (250 ml, 500 mmol), 250 mlwater and 100 ml brine. The mixture was extracted with TBME, washed withbrine, dried over MgSO₄.H₂O, filtered and evaporated to give a yellowoil which was purified on a silica gel column by eluting withhexane/0-5% TBME to yield 58.5 g of the title compound as a yellowliquid. TLC (Hex/TBME 99/1): R_(f)=0.25; HPLC: Rt_(H11)=1.921 min;ESIMS: 332, 334 [(M+H)⁺, 1Br]; ¹H-NMR (400 MHz, CDCl₃): 7.57 (d, 1H),2.68 (s, 3H), 1.00-0.84 (m, 15H).

c)(S)-2-(6-Bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-2-trimethylsilanyloxy-propionitrile

At first, the catalyst solution was prepared by dissolving water (54 mg,3.00 mmol) in 100 ml dry DCM (≤0.001% water). This wet DCM (44 ml, 1.32mmol water content) was added to a well stirred solution of titanium(IV)butoxide (500 mg, 1.47 mmol) in 20 ml dry DCM. The resulting clearsolution was refluxed for 1 h. This solution was then cooled to rt and2,4-di-tert-butyl-6-{[(E)-(S)-1-hydroxymethyl-2-methyl-propylimino]-methyl}-phenol[CAS 155052-31-6] (469 mg, 1.47 mmol) was added. The resulting yellowsolution was stirred at rt for 1 h. This catalyst solution (0.023 M,46.6 ml, 1.07 mmol) was added to a solution of1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-ethanone (35.53 g,107 mmol) and trimethylsilyl cyanide (12.73 g, 128 mmol) in 223 ml dryDCM. The mixture was stirred for 2 days and evaporated to give 47 g ofthe crude title compound as an orange oil. HPLC: Rt_(H12)=2.773 min;ESIMS: 431, 433 [(M+H)⁺, 1Br]; ¹H-NMR (400 MHz, CDCl₃): 7.46 (d, 1H),2.04 (s, 3H), 1.00 (t, 9H), 1.03-0.87 (m, 15H), 0.20 (s, 9H).

d)(R)-1-Amino-2-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-propan-2-olhydrochloride

Borane dimethyl sulfide complex (16.55 g, 218 mmol) was added to asolution of crude(S)-2-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-2-trimethylsilanyloxy-propionitrile(47 g, 109 mmol) in 470 ml THF. The mixture was refluxed for 2 h. Theheating bath was removed and the reaction mixture was quenched bycareful and dropwise addition of MeOH. After the evolution of gas hadceased, aq. 6M HCl (23.6 ml, 142 mmol) was added slowly. The resultingsolution was evaporated and the residue was dissolved in MeOH andevaporated (twice) to yield 44.5 g of a yellow foam, pure enough forfurther reactions. HPLC: Rt_(H1)=2.617 min; ESIMS: 363, 365 [(M+H)⁺,1Br]; ¹H-NMR (400 MHz, CDCl₃): 7.93 (s, br, 3H), 7.53 (d, 1H), 6.11 (s,br, 1H), 3.36-3.27 (m, 1H), 3.18-3.09 (m, 1H), 1.53 (s, 3H), 0.99-0.81(m, 15H).

e)(R)—N-(2-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2-hydroxypropyl)-4-nitrobenzenesulfonamide

To a solution of crude(R)-1-amino-2-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-propan-2-01hydrochloride (43.5 g, 109 mmol) in 335 ml THF was added a solution ofNaHCO₃ (21.02 g, 250 mmol) in 500 ml water. The mixture was cooled to0-5° C. and a solution of 4-nitrobenzenesulfonyl chloride (26.5 g, 120mmol) in 100 ml THF was added in a dropwise. The resulting emulsion wasstirred overnight while allowing the temperature to reach rt. Themixture was extracted with TBME. The organic layer was dried withMgSO₄.H₂O, filtered and evaporated to give an orange resin which waspurified on a silca gel column by eluting with Hexanes/10-20% EtOAc toyield 37.56 g of the title compound as a yellow resin. TLC (Hex/EtOAc3/1) R_(f)=0.34; HPLC: Rt_(H11)=1.678 min; ESIMS: 548, 550 [(M+H)⁺,1Br]; ¹H-NMR (400 MHz, DMSO-d₆): 8.40 (d, 2H), 8.06 (t, 1H), 7.97 (d,2H), 7.45 (d, 1H), 5.42 (s, 1H), 3.23 (d, 2H), 1.44 (s, 3H) 0.97-0.81(m, 15H); Chiral HPLC (Chiralpak AD-H 1213, UV 210 nm): 90% ee.

f)6-Bromo-3-fluoro-2-[(S)-2-methyl-1-(4-nitro-benzenesulfonyl)-aziridin-2-yl]-4-triethylsilanyl-pyridine

A solution of triphenylphosphine (21.55 g, 82 mmol) and(R)—N-(2-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2-hydroxypropyl)-4-nitrobenzenesulfonamide(37.56 g, 69 mmol) in 510 ml THF was cooled to 4° C. A solution ofdiethyl azodicarboxylate in toluene (40% by weight, 38.8 g, 89 mmol) wasadded in a dropwise while maintaining the temperature below 10° C. Thecooling bath was removed and the rm was stirred at rt for 1 h. Thereaction mixture was diluted with approx. 1000 ml toluene and THF wasremoved by evaporation at the rotavap. The resulting toluene solution ofcrude product was pre-purified on a silca gel column by eluting withhexanes/5-17% EtOAc. Purest fractions were combined, evaporated andcrystallized from TBME/hexane to yield 29.2 g of the title compound aswhite crystals.

HPLC: Rt_(H11)=2.546 min; ESIMS: 530, 532 [(M+H)⁺, 1Br]; ¹H-NMR (400MHz, CDCl₃): 8.40 (d, 2H), 8.19 (d, 2H), 7.39 (d, 1H), 3.14 (s, 1H),3.02 (s, 1H), 2.01 (s, 3H) 1.03-0.83 (m, 15H); α[D] −35.7° (c=0.97,DCM).

g)6-Bromo-3-fluoro-2-[(S)-2-methyl-1-(4-nitro-benzenesulfonyl)-aziridin-2-yl]-pyridine

Potassium fluoride (1.1 g, 18.85 mmol) was added to a solution of6-bromo-3-fluoro-2-[(S)-2-methyl-1-(4-nitro-benzenesulfonyl)-aziridin-2-yl]-4-triethylsilanyl-pyridine(5 g, 9.43 mmol) and AcOH (1.13 g, 9.43 mmol) in 25 ml THF. DMF (35 ml)was added and the suspension was stirred for 1 h at rt. The reactionmixture was poured onto a mixture of sat. aq. NaHCO₃ and TBME. Thelayers were separated and washed with brine and TBME. The combinedorganic layers were dried over MgSO₄.H₂O, filtered and evaporated togive a yellow oil which was crystallized from TBME/hexane to yield 3.45g of the title compound as white crystals.

HPLC: Rt_(H13)=2.612 min; ESIMS: 416, 418 [(M+H)⁺, 1Br]; ¹H-NMR (400MHz, CDCl₃): 8.41 (d, 2H), 8.19 (d, 2H), 7.48 (dd, 1H), 7.35 (t, 1H),3.14 (s, 1H), 3.03 (s, 1H), 2.04 (s, 3H); α[D]-35.7° (c=0.89, DCM).

h)(R)-2-[(R)-2-(6-Bromo-3-fluoro-pyridin-2-yl)-2-(4-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionicacid ethyl ester

A solution of (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acidethyl ester (11.93 g, 64.1 mmol) in DMF (158 ml) was evacuated/flushedwith nitrogen twice. A solution of KOtBu (6.21 g, 55.5 mmol) in DMF (17ml) was added in a dropwise while maintaining a reaction temperature ofca 25° C. using cooling with a water bath. After 15 min solid6-bromo-3-fluoro-2-[(S)-2-methyl-1-(4-nitro-benzenesulfonyl)-aziridin-2-yl]-pyridine(17.78 g, 42.7 mmol) was added and stirring was continued for 3 h. Thereaction mixture was poured onto a mixture of 1M HCl (56 ml), brine andTBME. The layers were separated, washed with brine and TBME. Thecombined organic layers were dried over MgSO₄.H₂O, filtered andevaporated. The crude reaction product was purified via chromatographyon silica gel (hexanes/25-33% TBME) to yield 16.93 g of the titlecompound as a yellow resin that was contaminated with an isomericside-product (ratio 70:30 by ¹H-NMR).

HPLC: Rt_(H13)=2.380 min; ESIMS: 602, 604 [(M+H)⁺, 1Br]; ¹H-NMR (400MHz, CDCl₃): 8.32 (d, 2H), 8.07 (d, 2H), 7.46-7.41 (m, 1H), 7.30-7.23(m, 1H), 6.92 (s, 1H), 3.39-4.30 (m, 2H), 3.95 (d, 1H), 3.84 (d, 1H),1.68 (s, 3H), 1.56 (s, 3H), 1.40-1.34 (m, 3H)+isomeric side-product.

i)(R)-2-[(R)-2-(6-Bromo-3-fluoro-pyridin-2-yl)-2-(4-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionamide

A solution of(R)-2-[(R)-2-(6-bromo-3-fluoro-pyridin-2-yl)-2-(4-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionicacid ethyl ester (16.93 g, 28.1 mmol) in a NH₃/MeOH (7M, 482 ml) wasstirred at 50° C. in a sealed vessel for 26 h. The reaction mixture wasevaporated and the residue was crystallized from DCM to yield 9.11 g ofthe title compound as colorless crystals.

HPLC: Rt_(H13)=2.422 min; ESIMS: 573, 575 [(M+H)⁺, 1Br]; ¹H-NMR (400MHz, CDCl₃): 8.33 (d, 2H), 8.06 (d, 2H), 7.42 (dd, 1H), 7.30-7.26 (m,1H), 7.17 (s, br, 1H), 6.41 (s, 1H), 5.57 (s, br, 1H), 4.15 (m, 2H),1.68 (s, 3H), 1.65 (s, 3H).

j)N—[(R)-1-(6-Bromo-3-fluoro-pyridin-2-yl)-2-((R)-1-cyano-2,2,2-trifluoro-1-methyl-ethoxy)-1-methyl-ethyl]-4-nitro-benzenesulfonamide

A suspension of(R)-2-[(R)-2-(6-bromo-3-fluoro-pyridin-2-yl)-2-(4-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionamide(8.43 g, 14.70 mmol) and triethylamine (5.12 ml, 36.8 mmol) in 85 ml DCMwas cooled to 0-5° C. Trifluoroacetic anhydride (2.49 ml, 17.64 mmol)was added dropwise over 30 min. Additional triethylamine (1.54 ml, 11.07mmol) and trifluoroacetic anhydride (0.75 ml, 5.29 mmol) were added tocomplete the reaction. The reaction mixture was quenched by addition of14 ml aqueous ammonia (25%) and 14 ml water. The emulsion was stirredfor 15 min, more water and DCM were added and the layers were separated.The organic layer was dried with MgSO₄ H₂O, filtered and evaporated.Purification by column chromatography on a silica gel (hexanes/10-25%EtOAc) gave 8.09 g of the title compound as a yellow resin.

HPLC: Rt_(H13)=3.120 min; ESIMS: 555, 557 [(M+H)⁺, 1Br]; ¹H-NMR (400MHz, CDCl₃): 8.35 (d, 2H), 8.11 (d, 2H), 7.50 (dd, 1H), 7.32 (dd, 1H),6.78 (s, 1H), 4.39 (d 1H), 4.22 (d, 1H), 1.68 (s, 6H).

k)(2R,5R)-5-(6-Bromo-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine

A solution ofN—[(R)-1-(6-bromo-3-fluoro-pyridin-2-yl)-2-((R)-1-cyano-2,2,2-trifluoro-1-methyl-ethoxy)-1-methyl-ethyl]-4-nitro-benzenesulfonamide(9.18 g, 16.53 mmol) and N-acetylcysteine (5.40 g, 33.10 mmol) in 92 mlethanol was evacuated and flushed with nitrogen. K₂CO₃ (4.57 g, 33.1mmol) was added and the mixture was stirred at 80° C. for 3 days. Thereaction mixture was concentrated in vacuo to about ¼ of the originalvolume and partitioned between water and TBME. The organic layer waswashed with 10% aq. K₂CO₃ solution, dried over Na₂SO₄, filtered andevaporated to give a yellow oil. Column chromatography on silica(hexanes/14-50% (EtOAc:MeOH 95:5)) gave 4.55 g of the title compound asan off-white solid.

HPLC: Rt_(H3)=2.741 min; ESIMS: 370, 372 [(M+H)⁺, 1Br]; ¹H-NMR (400 MHz,DMSO-d₆): 7.71-7.62 (m, 2H), 5.97 (s, br, 2H), 4.02 (d 1H), 3.70 (d,1H), 1.51 (s, 3H), 1.47 (s, 3H).

Examples 25 to 34

The compounds in Table 9 were prepared by similar procedures as forExample 11 or Example 24; Example 28 required intermediate [(2R,5S)-5-(6-Amino-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoro-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester from Example 24 (step b, second isomer).

TABLE 9 MS [m/z; Example Compound ¹H-NMR (M + 1)⁺] 25

  5-Methoxy-3-methyl-pyridine-2-carboxylic acid[6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide (δ;DMSO-d₆, 600 MHz): 10.40 (br. s, 1H, NH), 8.28 (d, 1H) 8.18 (br. d, 1H),7.72 (t, 1H), 7.44 (d, 1H), 6.00 (br. s, 2H, NH₂), 4.11 (d, 1H, AB),3.91 (s, 3H), 3.75 (d, 1H, AB), 2.70 (s, 3H), 1.50 (s, 3H), 1.49 (s,3H). LCMS: Rt_(H4) = 0.88; [M + 1]⁺ = 456.4 26

  3-Amino-5-(2,2,2-trifluoro-ethoxy)- pyrazine-2-carboxylic acid[6-((3R,6R)-5-amino-3,6- dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide (δ; DMSO-d₆ + 1 dropTFA, 600 MHz): 10.10 (br. s, 1H, NH), 9.68 (s, 1H, NH- amidine), 9.50(s, 1H, NH-amidine), 8.26 (dd, 1H), 8.20-7.70 (broad, 2H, NH₂-pyrazine),7.92 (t, 1H), 7.67 (s, 1H), 5.02 (q, 2H), 4.40 (d, 1H, AB), 4.25 (d, 1H,AB), 1.70 (s, 3H), 1.68 (s, 3H). LCMS: Rt_(H4) = 0.93; [M + 1]⁺ = 526.327

  3-Amino-5-cyano-pyridine-2-carboxylic acid[6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide (δ; DMSO-d₆,600 MHz): 10.30 (br. s, 1H, NH), 8.23 (d, 1H), 8.12 (br. d, 1H), 7.75(t, 1H), 7.69 (d, 1H), 7.31 (br. s, 2H, NH₂- pyridine), 5.95 (br. s, 2H,NH₂-amidine), 4.11 (d, 1H, AB), 3.72 (d, 1H, AB), 1.50 (s, 3H), 1.49 (s,3H). LCMS: Rt_(H4) = 0.86; [M + 1]⁺ = 452.1 28

  3-Chloro-5-cyano-pyridine-2-carboxylic acid[6-((3S,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide (δ;DMSO-d₆, 600 MHz): 11.10 (s, 1H, NH), 9.10 (s, 1H), 8.79 (s, 1H), 8.10(br. d, 1H), 7.72 (br. t, 1H), 5.90 (br. s, 2H, NH₂-amidine), 4.20 (br.s, 1H, AB), 3.70 (br. s, 1H, AB), 1.60 (s, 3H), 1.50 (s, 3H). LCMS:Rt_(H4) = 0.77; [M + 1]⁺ = 471.1 29

  5-Difluoromethoxy-3-methyl-pyridine-2-carboxylic acid[6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide (δ;DMSO-d₆, 600 MHz): 10.45 (br. s, 1H, NH), 8.44 (s, 1H), 8.18 (d, 1H),7.76 (s, 1H), 7.72 (t, 1H), 7.45 (t, 1H), 5.90 (br. s, 2H, NH₂), 4.11(d, 1H, AB), 3.72 (d, 1H, AB), 2.68 (s, 3H), 1.50 (s, 3H), 1.49 (s, 3H).LCMS: Rt_(H4) = 0.90; [M + 1]⁺ = 492.3 30

  3-Chloro-5-difluoromethoxy-pyridine-2-carboxylic acid[6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide (δ;DMSO-d₆, 600 MHz): 10.90 (br. s, 1H, NH), 8.59 (s, 1H), 8.11 (d, 1H),8.10 (s, 1H), 7.72 (t, 1H), 7.49 (t, 1H), 5.88 (br. s, 2H, NH₂), 4.11(d, 1H, AB), 3.72 (d, 1H, AB), 1.50 (s, 3H), 1.49 (s, 3H). LCMS: Rt_(H4)= 0.85; [M + 1]⁺ = 512.2 31

  3,5-Dichloro-pyridine-2-carboxylic acid [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide (δ; DMSO-d₆,400 MHz): 10.92 (br. s, 1H, NH), 8.73 (br. s, 1H), 8.44 (d, 1H), 8.12(dd, 1H), 7.73 (dd, 1H), 5.88 (br. s, 2H, NH2), 4.11 (d, 1H, AB), 3.72(d, 1H, AB), 1.51 (s, 3H), 1.48 (s, 3H). LCMS: Rt_(H4) = 0.86; [M + 1]⁺= 480, 482, 484 32

  5-Fluoromethoxy-3-methyl-pyridine-2-carboxylic acid[6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide (δ;DMSO-d₆, 400 MHz): 10.42 (br. s, 1H, NH), 8.43 (d, 1H), 8.16 (dd, 1H),7.73 (dd, 1H), 7.66 (d, 1H), 6.04 (d, 2H, CH₂F), 5.91 (br. s, 2H, NH2),4.13 (d, 1H, AB), 3.74 (d, 1H, AB), 2.70 (s, 3H), 1.51 (s, 3H), 1.49 (s,3H). LCMS: Rt_(H4) = 0.87; [M + 1]⁺ = 474 33

  5-Methyl-pyrazine-2-carboxylic acid [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide (δ; DMSO-d₆,400 MHz): 10.19 (br. s, 1H, NH), 9.22 (d, 1H), 8.73 (d, 1H), 8.18 (dd,1H), 7.79 (dd, 1H), 5.92 (br. s, 2H, NH2), 4.15 (d, 1H, AB), 3.76 (d,1H, AB), 2.66 (s, 3H), 1.52 (s, 3H), 1.50 (s, 3H). LCMS: Rt_(H4) = 0.78;[M + 1]⁺ = 427 34

  3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid[6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide (δ;DMSO-d₆, 400 MHz): 11.15 (br. s, 1H, NH), 9.06 (s, 1H), 8.69 (s, 1H),8.13 (dd, 1H), 7.75 (dd, 1H), 5.88 (br. s, 2H, NH2), 4.13 (d, 1H, AB),3.73 (d, 1H, AB), 1.52 (s, 3H), 1.49 (s, 3H). LCMS: Rt_(H4) = 0.93; [M +1]⁺ = 514, 516

Examples 35 to 36

The compounds in Table 10 can be prepared by a procedure analogous tothat used in Example 16.

TABLE 10 MS ¹H-NMR [m/z; Example Compound (δ; DMSO-d₆) (M + 1)⁺] 35

  3-Chloro-5-cyano-pyridine-2-carboxylic acid[4-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide 11.23 (brs, 1H), 9.08 (d, 1H), 8.79 (d, 1H), 8.33-8.30 (m, 2H), 6.23 (br s, 2H),3.97 (d, 1H), 3.82 (d, 1H), 1.49 (s, 3H), 1.44 (s, 3H) UPLCMS: Rt_(H4) =0.78 [M + 1] = 471.2 36

  3-Chloro-5-difluoromethoxy-pyridine-2-carboxylic acid[4-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide 10.95 (s,1H), 8.56 (d, 1H), 8.37-8.25 (m, 2H), 8.09 (d, 1H), 7.48 (t, 1H), 6.23(br s, 2H), 3.97 (d, 1H), 3.82 (d, 1H), 1.49 (s, 3H), 1.44 (s, 3H)UPLCMS: Rt_(H4) = 0.89 [M + 1] = 512.2

Example 37: 5-Cyano-3-methyl-pyridine-2-carboxylic acid[4-((R)-5-amino-6,6-bis-fluoromethyl-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide

a)2-[2-(2-Bromo-5-fluoro-pyridin-4-yl)-2-(2-nitro-benzenesulfonylamino)-propoxy]-3-fluoro-2-fluoromethyl-propionicacid ethyl ester

A solution of 3-fluoro-2-fluoromethyl-2-hydroxy-propionic acid ethylester (see Intermediates Hydroxyester 1, 0.606 g, 3.60 mmol) in DMF (7ml) was predried over activated 4 Å molecular sieves, then a suspensionof NaH (0.135 g of a 60% dispersion in mineral oil, 3.36 mmol) was addedand the reaction mixture was stirred at rt for 10 min. A solution of2-bromo-5-fluoro-4-[2-methyl-1-(2-nitro-benzenesulfonyl)-aziridin-2-yl]-pyridine(see Example 16, step g, 1.0 g, 2.403 mmol) in DMF (7 ml, soln. predriedover activated 4 Å molecular sieves) was slowly added. The reactionmixture was stirred at rt for 3.5 h, then quenched with aq. 1N HCl soln.and diluted with H₂O and TBME. The phases were separated and the aq.layer was twice reextracted with TBME. The combined organic layers werewashed with H₂O, dried over Na₂SO₄, filtered and concentrated. Theresulting crude title compound was purified by NP-HPLC (Alltech GromSaphir65 Si 10 μm column, 250×50 mm, gradient n-heptane:EtOAc 75:25 to0:100).

HPLC: Rt_(H4)=1.18 min; ESIMS [M+H]⁺=584, 586 (1Br);

¹H-NMR (400 MHz, DMSO-d₆): δ 8.76 (s, 1H), 8.21 (d, 1H), 7.94-7.92 (m,2H), 7.88-7.75 (m, 2H), 7.70 (d, 1H), 4.85-4.46 (m, 4H), 4.20 (q, 2H),4.04 (d, 1H), 3.83 (d, 1H), 1.62 (s, 3H), 1.21 (t, 3H).

b)2-[2-(2-Bromo-5-fluoro-pyridin-4-yl)-2-(2-nitro-benzenesulfonylamino)-propoxy]-3-fluoro-2-fluoromethyl-propionamide

A solution of2-[2-(2-bromo-5-fluoro-pyridin-4-yl)-2-(2-nitro-benzenesulfonylamino)-propoxy]-3-fluoro-2-fluoromethyl-propionicacid ethyl ester (970 mg, 1.660 mmol) and 7M NH₃ in MeOH (10 ml) wasstirred in a in a sealed glass vial at 55° C. for 20 h. Another 3 ml of7N NH₃/MeOH were added and stirring was continued for 16 h at 55° C. Thereaction mixture was concentrated and yielded the title compound as ayellow solid that was used in the next step without furtherpurification.

HPLC: Rt_(H4)=0.95 min; ESIMS [M+H]⁺=555, 557 (1Br);

¹H-NMR (400 MHz, DMSO-d₆): δ 9.01 (s, 1H), 8.25 (d, 1H), 7.99-7.90 (m,2H), 7.85-7.58 (m, 5H), 4.73-4.51 (m, 4H), 3.96 (d, 1H), 3.90 (d, 1H),1.58 (s, 3H).

c)N—O-(2-Bromo-5-fluoro-pyridin-4-yl)-2-(cyano-bis-fluoromethyl-methoxy)-1-methyl-ethyl]-2-nitro-benzenesulfonamide

To a solution of2-[2-(2-bromo-5-fluoro-pyridin-4-yl)-2-(2-nitro-benzenesulfonylamino)propoxy]-3-fluoro-2-fluoromethyl-propionic acid ethyl ester (900 mg,1.621 mmol) in DCM (11 ml) was added NEt₃ (0.565 ml, 410 mg, 4.050mmol). The reaction mixture was cooled to 0° C., then TFA anhydride(0.275 ml, 408 mg, 1.945 mmol) was added dropwise. The reaction mixturewas allowed to warm to rt and to stir for 18 h. In order to obtaincomplete conversion, the reaction mixture was cooled again to 0° C. andmore TFA anhydride (0.450 ml, 670 mg, 3.190 mmol) followed by NEt₃(0.230 ml, 168 mg, 1.659 mmol) was added and the reaction mixture wasallowed to warm to rt and to stir for another 30 min.

The reaction mixture was diluted with sat. aq. Na₂CO₃ soln. and DCM. Thephases were separated and the aq. phase was twice reextracted with DCM.The combined organic phases were washed with brine, dried over Na₂SO₄,filtered and concentrated. The resulting crude title compound waspurified by NP-HPLC (Alltech Grom Saphir65 Si 10 μm column, 150×30 mm,gradient n-heptane:EtOAc 85:15 to 0:100).

HPLC: Rt_(H4)=1.09 min; ESIMS [M+H]⁺=537, 339 (1Br);

¹H-NMR (400 MHz, DMSO-d₆): δ 9.02 (s, 1H), 8.24 (d, 1H), 7.94-7.90 (m,2H), 7.87-7.75 (m, 2H), 7.61 (d, 1H), 4.95-4.48 (m, 4H), 4.14-4.02 (m,2H), 1.60 (s, 3H).

d)5-(2-Bromo-5-fluoro-pyridin-4-yl)-2,2-bis-fluoromethyl-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine

A solution ofN-[1-(2-bromo-5-fluoro-pyridin-4-yl)-2-(cyano-bis-fluoromethyl-methoxy)-1-methyl-ethyl]-2-nitro-benzenesulfonamide(840 mg, 1.563 mmol), N-acetyl-L-cysteine (510 mg, 3.13 mmol) and K₂CO₃(432 mg, 3.130 mmol) in abs. EtOH (10 ml) was stirred at 85° C. for 18h. N-acetyl-L-cysteine (250 mg, 1.533 mmol) and K₂CO₃ (210 mg, 1.519mmol) was added and stirring at 85° C. was continued for 18 h. Thereaction mixture was concentrated to ⅓ of its volume, quenched with 10%aq. K₂CO₃ soln. and 3× extracted with TBME. The combined org. phaseswere washed with sat. aq. NaHCO₃ soln, brine, dried over Na₂SO₄,filtered and concentrated to leave the crude title compound that waspurified by NP-HPLC (Alltech Grom Saphir65 Si 10 μm column, 150×30 mm,gradient n-heptane:EtOAc:MeOH 68:30:2 to 0:65:35),

HPLC: Rt_(H4)=0.57 min; ESIMS [M+H]⁺=352, 354 (1Br);

¹H-NMR (400 MHz, DMSO-d₆): δ 8.35 (d, 1H), 7.76 (d, 1H), 6.32 (br s,2H), 4.98-4.71 (m, 2H), 4.66-4.39 (m, 2H), 3.94 (dd, 1H), 3.82 (d, 1H),1.40 (s, 3H).

e) 5-Cyano-3-methyl-pyridine-2-carboxylic acid[4-(5-amino-6,6-bis-fluoromethyl-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide

A mixture of 5-cyano-3-methyl-pyridine-2-carboxylic acid amide (seeIntermediates Amide 1, 96 mg, 0.596 mmol),5-(2-bromo-5-fluoro-pyridin-4-yl)-2,2-bis-fluoromethyl-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine(210 mg, 0.596 mmol), Xantphos (31.1 mg, 0.054 mmol) and Cs₂CO₃ (272 mg,0.835 mmol) in dioxane (6 ml) was degassed with argon, Pd₂(dba)₃ (16.38mg, 0.018 mmol) was added and the reaction mixture was stirred at 60° C.for 16 h. More Pd₂(dba)₃ (8.19 mg, 0.009 mmol) and Xantphos (15.60 mg,0.027 mmol) was added and stirring was continued at 60° C. for 4 h. Thereaction mixture was filtered through celite and the celite pad rinsedwith DCM. The combined filtrates were concentrated and the resultingcrude title compound was purified by NP-HPLC (Alltech Grom Saphir65 Si10 μm column, 150×30 mm, gradient n-heptane:EtOAc:MeOH 68:30:2 to0:65:35), then by RP-HPLC (Waters SunFire C18 column, 5 μM, 30×100 mm,gradient 10 to 30% ACN+0.1% TFA) and obtained as a free base afterfiltration over an SCX cartridge.

HPLC: Rt_(H4)=0.72 min; ESIMS [M+H]⁺=433;

¹H-NMR (400 MHz, DMSO-d₆): δ 10.75 (s, 1H), 8.98 (s, 1H), 8.42 (s, 2H),8.28 (s, 1H), 6.20 (br s, 2H), 5.05-4.45 (m, 4H), 4.02-3.84 (m, 2H),2.58 (s, 3H), 1.45 (s, 3H)

f) 5-Cyano-3-methyl-pyridine-2-carboxylic acid[4-((R)-5-amino-6,6-bis-fluoromethyl-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide

Racemic (5-cyano-3-methyl-pyridine-2-carboxylic acid[4-(5-amino-6,6-bis-fluoromethyl-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amidewas separated into the pure enantiomers by preparative chiral HPLC(column: Chiralpak AD-H 20×250 mm, 5 uM; solvent: n-heptane/ethanol75:25; flow: 12 ml/min; detection at 220 nm). Enantiomer 1: Rt 8.964min. Enantiomer 2: Rt 16.220 min (determined by analytical HPLC usingChiralpak AD-H 250×4.6 mm, 5 uM column; solvent: n-heptane/ethanol/MeOH70:25:5+DEA; flow: 1.600 ml/min; detection at 220 nm).The absoluteconfiguration of enantiomer 2 was assigned (R) in analogy to similarstructures of which the configuration has been determined by X-raycrystallography.

¹H-NMR (400 MHz, DMSO-d₆): δ 10.76 (s, 1H), 8.98 (s, 1H), 8.42 (s, 2H),8.28 (s, 1H), 6.21 (br s, 2H), 5.02-4.45 (m, 4H), 3.95 (d, 1H), 3.89 (d,1H), 2.58 (s, 3H), 1.44 (s, 3H).

Example 38: 5-Cyano-3-methyl-pyridine-2-carboxylic acid[6-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide

a) 2-Bromo-5-fluoro-4-triethylsilanylpyridine

To a solution of diisopropylamine (25.3 g, 250 mmol) in THF (400 ml) wasadded n-BuLi (100 ml, 2.5 mol/L in hexanes) below −50° C. A solution of2-bromo-5-fluoropyridine (41.9 g, 238 mmol) in THF (60 ml) was added tothe LDA-solution at −78° C. in a dropwise manner below −63° C. After 60minutes at −78° C. triethylchlorosilane (44 ml, 262 mmol) was added in afast manner keeping the temperature below −50° C. The cooling bath wasremoved and the reaction mixture was allowed to reach −20° C. Thereaction mixture was poured on a mixture of 1M aq. HCl (250 ml) and aq.NH₄Cl (10%). Tert.-butyl methyl ether was added and the layers wereseparated. The organic phase was washed with brine, dried over magnesiumsulfate, filtered and evaporated to give a yellow liquid. Distillation(bp. 99-101° C., 0.5 mm Hg). afforded the title compound as a slightlyyellow liquid: 66.26 g (96% yield)

¹H-NMR (400 MHz, CDCl₃): 8.17 (s, 1H), 7.42 (d, 1H), 1.01-0.97 (m, 9H),0.92-0.87 (m, 6H).

b)1-(6-Bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-2,2-difluoro-ethanone

To a freshly prepared solution of LDA (6.25 mmol) in THF (5 ml) wasadded dropwise a solution of 2-bromo-5-fluoro-4-triethylsilanylpyridine(1.6 g, 5.51 mmol) in THF (12 ml) at −78° C. Stirring was continued at−78° C. for 3 hours. Ethyl 2,2-difluoroacetate (0.58 ml, 5.51 mmol) wasadded dropwise and the solution was stirred at −78° C. for 3 hours. Thereaction mixture was quenched with sat. ammonium chloride solution (20ml) and ethyl acetate was added. The organic phase was washed withbrine, dried over sodium sulfate, filtered and evaporated. The crudebrown oil (2.11 g) was chromatographed over silica gel(cyclohexane/ethyl acetate) to give the title compound. 1.53 g (75%yield, mixture of ketone and hydrate form).

TLC (cyclohexane/ethyl acetate 10:1) R_(f)=0.26; ¹H-NMR (400 MHz,CDCl₃): 7.70 (d, 1H), 6.96 (t, 1H, CHF₂)), 1.02-0.98 (m, 9H), 0.96-0.92(m, 6H).

c) (S)-2-Methyl-propane-2-sulfinicacid[1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-2,2-difluoro-ethylidene]-amide

A mixture of1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-2,2-difluoro-ethanone(9.8 g, 26.6 mmol), (S)-2-methylpropane-2-sulfinamide (3.23 g, 26.6mmol) and tetraethoxytitanium (13.81 ml, 53.2 mmol) in THF (66.5 ml) wasstirred at 80° C. in 3 capped microwave vials (3×25 ml) for 3 hours. Thecold reaction mixture was poured into ice cold water and the precipitatewas filtered through a pad of hyflo and washed thoroughly with ethylacetate. The organic phase was washed with brine, dried over sodiumsulfate, filtered and evaporated. The crude product (12.5 g) waschromatographed over silica gel (cyclohexane:ethyl acetate 5:1) toafford the title compound. 7.96 g (63% yield).

TLC (cyclohexane/ethyl acetate 5:1) R_(f)=0.65; LCMS Rt_(H4)=1.53 min.(100% pure, ESI+ 471, 473); ¹H-NMR (400 MHz, CDCl₃): 7.50 (d, 1H), 6.49(t, 1H, CHF₂), 1.33 (s, 9H), 1.03-0.98 (m, 9H), 0.93-0.89 (m, 6H).

d) (S)-2-Methyl-propane-2-sulfinicacid[(S)-1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-1-difluoromethyl-allyl]-amideand (S)-2-Methyl-propane-2-sulfinicacid[(R)-1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-1-difluoromethyl-allyl]-amide

Vinylmagnesium bromide 1M in THF (2.3 ml, 2.3 mmol) was added todichloromethane (5 ml) and the solution was cooled down to −78° C.(S)-2-Methyl-propane-2-sulfinicacid[1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-2,2-difluoro-ethylidene]-amide(500 mg, 1.06 mmol) in dichloromethane (5 ml) was added dropwise to theabove solution keeping the temperature below −65° C. After 30 minutesthe reaction was quenched at −78° C. with ammonium chloride solution(10%) and the reaction mixture was extracted with TBME. The organiclayer was washed with brine, dried over sodium sulfate, filtered andevaporated. 620 mg (quant. yield) as a 4:1 mixture of diastereoisomersused without purification in the next step.

TLC (cyclohexane/ethyl acetate 10:1) R_(f)=0.15 and (cyclohexane/ethylacetate 10:1);

R_(f)=0.10; LCMS Rt_(H4)=1.50 min. (ESI+ 499, 501); ¹H-NMR (400 MHz,CDCl₃): 8.56 (s, 1H, NH), 7.47 and 7.45 (d, 1H), 6.60-6.30 (t, 1H,CHF₂), 6.25-6.16 (m, 1H), 5.65-5.30 (m, 2H), 1.34 and 1.31 (s, 9H),0.99-0.96 (m, 9H), 0.90-0.84 (m, 6H).

e) (S)-2-Methyl-propane-2-sulfinic acid[(R)-1-(6-bromo-3-fluoro-4-triethylsilylanyl-pyridin-2-yl)-2,2-difluoro-1-hydroxymethyl-ethyl]-amideand (S)-2-Methyl-propane-2-sulfinic acid[(S)-1-(6-bromo-3-fluoro-4-triethylsilylanyl-pyridin-2-yl)-2,2-difluoro-1-hydroxymethyl-ethyl]-amide

A mixture of (S)-2-methyl-propane-2-sulfinicacid[(S)-1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-1-difluoromethyl-allyl]-amideand (S)-2-Methyl-propane-2-sulfinicacid[(R)-1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-1-difluoromethyl-allyl]-amidefrom step d) (5.137 g, 10.28 mmol) was dissolved in dichloromethane (77ml) and methanol (25.7 ml), sodium bicarbonate (1.296 g, 15.43 mmol) wasadded and the reaction mixture was cooled to −78° C. Ozone was bubbledthrough the solution until a blue coloration appeared (4 hr). Excessozone was blown out with nitrogen until the blue color has disappeared.Sodium borohydride (1.945 g, 51.4 mmol) was added to the solution andthe reaction mixture was stirred at −78° C. for 3 hours. The reactionmixture was diluted with TBME and 2N HCl to destroy excess sodiumborohydride. The organic layer was washed carefully with 1N HCl solutionand brine, dried over sodium sulfate, filtered and evaporated. 6.15 gyellow oil. The crude product was chromatographed over silica gel (120g, cyclohexane/ethyl acetate 3:1) to give the title compounds:

(S)-2-Methyl-propane-2-sulfinic acid[(R)-1-(6-bromo-3-fluoro-4-triethylsilylanyl-pyridin-2-yl)-2,2-difluoro-1-hydroxymethyl-ethyl]-amide

2.36 g (45.6% yield).

TLC (cyclohexane/ethyl acetate 3:1) R_(f)=0.24; LCMS Rt_(H4)=1.36 min.(93% pure, ESI+ 503, 505);

¹H-NMR (400 MHz, CDCl₃): 7.46 (d, 1H), 6.24 (t, 1H, CHF₂), 4.60 (br. s,1H, NH), 4.47 (br. s, 2H, AB), 3.48 (br. s, 1H, OH), 1.32 (s, 9H), 0.99(t, 9H), 0.89 (q, 6H).

(S)-2-Methyl-propane-2-sulfinic acid[(S)-1-(6-bromo-3-fluoro-4-triethylsilylanyl-pyridin-2-yl)-2,2-difluoro-1-hydroxymethyl-ethyl]-amide

1.72 g (33.2% yield).

TLC (cyclohexane/ethyl acetate 3:1) R_(f)=0.31;

LCMS Rt_(H4)=1.43 min. (100% pure, ESI+ 503, 505);

¹H-NMR (400 MHz, CDCl₃): 7.47 (d, 1H), 6.62 (br. s, 1H), 6.23 (t, 1H,CHF₂), 4.51-4.48 (d, 1H, AB), 4.36-4.32 (d, 1H, AB), 1.42 (s, 9H), 0.99(t, 9H), 0.89 (q, 6H).

f)(R)-2-Amino-2-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-3,3-difluoro-propan-1-ol

To a solution of (S)-2-methyl-propane-2-sulfinic acid[(R)-1-(6-bromo-3-fluoro-4-triethylsilylanyl-pyridin-2-yl)-2,2-difluoro-1-hydroxymethyl-ethyl]-amide(2.3 g, 4.57 mmol) in dichloromethane (45 ml) was added HCl (5.48 ml,16.45 mmol, 3 molar in methanol) and the reaction mixture was stirredfor 5 hours at room temperature. The solvent was removed in vacuo andthe residue diluted with ethyl acetate and poured onto a mixture ofammonia 2N/ice. The layers were separated and the organic phase waswashed with water and brine, dried over sodium sulfate, filtered andevaporated. 2.15 g. Used in next step without further purification.

LCMS Rt_(H4)=1.18 min. (94% purity, ESI+ 399, 401); ¹H-NMR (400 MHz,CDCl₃): 7.43 (d, 1H), 6.16 (t, 1H, CHF₂), 4.13-4.10 (d, 1H, AB),3.99-3.93 (d, 1H, AB), 2.52 (br. s, 3H, OH, NH₂), 0.99 (t, 9H), 0.89 (q,6H).

g)N—[(R)-1-(6-Bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-2,2-difluoro-1-hydroxymethyl-ethyl]-2-chloro-acetamide

To a solution of(R)-2-amino-2-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-3,3-difluoro-propan-1-ol(2.15 g, 5.38 mmol) in dichloromethane (14.55 ml) was added an aq.sodium carbonate solution (14.55 ml, 10% aq. solution) at 0° C.2-Chloroacetyl chloride (0.518 ml, 6.46 mmol) was added dropwise at 0°C. and the ice bath was removed after the addition. The reaction mixturewas stirred at rt for 15 min. Methanol was added and the reactionmixture was stirred at 50° C. for 10 min. The reaction mixture wasdiluted with dichloromethane and water. The mixture was extracted withdichloromethane, dried over sodium sulfate, filtered and evaporated. Thecrude light yellow oil (2.91 g) was chromatographed over silica gel (40g redisep column, cyclohexane/ethyl acetate 10-70%) to give the titlecompound. 2.32 g (91% yield).

TLC (cyclohexane/ethyl acetate 2:1) R_(f)=0.53; LCMS Rt_(H4)=1.30 min.(ESI+ 475, 477, 479);

¹H-NMR (400 MHz, CDCl₃): 8.17 (br. s, 1H, NH), 7.47 (d, 1H), 6.58 (t,1H, CHF₂), 4.64-4.55 (m, 1H, AB), 4.20-4.12 (m, 3H, AB), 0.98 (t, 9H),0.89 (q, 6H).

h)(R)-5-(6-Bromo-3-fluoro-pyridin-2-yl)-5-difluoromethyl-morpholin-3-one

To a solution ofN—[(R)-1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-2,2-difluoro-1-hydroxymethyl-ethyl]-2-chloro-acetamide(2.32 g, 4.88 mmol) in t-butanol (50 ml) was added potassiumtert-butoxide (7.31 ml, 7.31 mmol, 1M in THF) and the solution wasstirred in a closed vial for 18 h at 100° C. The reaction mixture wasdiluted with ethyl acetate, washed with water, sat. NaHSO₄ solution andbrine, dried over sodium sulfate, filtered and evaporated. The crudeproduct (2.36 g) was chromatographed over silica gel (24 g redisepcolumn, cyclohexane/ethyl acetate 10-80%) to give the title compound.1.13 g (71% yield). Triethylsilylated lactam (640 mg) was recovered.

TLC (cyclohexane/ethyl acetate 1:1) R_(f)=0.25;

LCMS Rt_(H4)=0.79 min. (ESI+ 325, 327); ¹H-NMR (400 MHz, CDCl₃):7.59-7.57 (m, 1H), 7.51 (br. s, 1H, NH), 7.45-7.42 (m, 1H), 6.23 (t, 1H,CHF₂), 4.86 (d, 1H, AB), 4.38 (d, 1H, AB), 4.16 (d, 1H, AB), 3.97 (d,1H, AB).

i)(R)-5-(6-Bromo-3-fluoro-pyridin-2-yl)-5-difluoromethyl-morpholin-3-thione

To a solution of(R)-5-(6-bromo-3-fluoro-pyridin-2-yl)-5-difluoromethyl-morpholin-3-one(1.13 g, 3.48 mmol) in pyridine (34.8 ml) was added phosphorouspentasulfide, the vial was sealed and the reaction mixture was stirredat 100° C. for 2 h. The reaction mixture was diluted with 2M HClsolution and ethyl acetate. The organic layer was washed with brine,dried over sodium sulfate, filtered and evaporated. The crude product(1.4 g) was used in the next step without purification.

LCMS Rt_(H4)=0.98 min. (ESI+ 341, 343); ¹H-NMR (400 MHz, CDCl₃): 9.40(br. s, 1H, NH), 7.62 (dd, 1H), 7.45 (dd, 1H), 6.25 (t, 1H, CHF₂), 4.93(dd, 1H, AB), 4.79 (d, 1H, AB), 4.44 (d, 1H, AB), 4.00 (dd, 1H, AB).

j)(R)-5-(6-Bromo-3-fluoro-pyridin-2-yl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine

To a solution of(R)-5-(6-bromo-3-fluoro-pyridin-2-yl)-5-difluoromethyl-morpholin-3-thione(611 mg, 1.79 mmol) in methanol (15 ml) was added ammonia (5.12 ml, 35.8mmol, 7M in methanol), the vial was sealed and the reaction mixture wasstirred at rt for 20 h. The reaction mixture was diluted with ethylacetate. The organic layer was washed with aq. sodium thiosulfatesolution (10%), water and brine, dried over sodium sulfate, filtered andevaporated. The crude product (640 mg) was chromatographed over silicagel (14 g, dichloromethane/methanol 95/5+0.5% NH₃) to give the titlecompound. 180 mg (31% yield).

LCMS Rt_(H4)=0.55 min. (ESI+ 325, 327); ¹H-NMR (400 MHz, CDCl₃): 7.45(dd, 1H), 7.32 (dd, 1H), 6.31 (t, 1H, CHF₂), 4.38 (d, 1H, AB), 4.22 (d,1H, AB), 4.15 (d, 1H, AB), 4.10 (d, 1H, AB), 3.0-1.5 (very br. s, 2H,NH₂).

k)[(R)-5-(6-Bromo-3-fluoro-pyridin-2-yl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

A solution of(R)-5-(6-bromo-3-fluoro-pyridin-2-yl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine(180 mg, 0.555 mmol), BOC-anhydride (121 mg, 0.555 mmol) and Hünig'sbase (108 mg, 0.833 mmol) in dichloromethane (5.5 ml) was stirred at rtfor 18 h. The reaction mixture was diluted dichloromethane and washedwith aq. saturated bicarbonate solution and brine, dried over sodiumsulfate, filtered and evaporated. The crude product (352 mg light yellowsolid) was chromatographed over silica gel (4 g, cyclohexane/ethylacetate 5-40%) to give the title compound. 190 mg (81% yield).

TLC (cyclohexane/ethyl acetate 3:1) R_(f)=0.30;

LCMS Rt_(H4)=1.11 min. (93% purity, ESI+ 424, 426); ¹H-NMR (400 MHz,DMSO-d₆): 9.97 (s, 1H, NH), 7.77-7.75 (m, 2H), 6.40 (t, 1H, CHF₂), 4.51(br. s, 2H, AB), 4.21 (d, 1H, AB), 3.88 (d, 1H, AB), 1.41 (s, 9H).

l)((R)-5-{6-[(5-Cyano-3-methyl-pyridine-2-carbonyl)-amino]-3-fluoro-pyridin-2-yl}-5-difluoromethyl-4,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester

A mixture of[(R)-5-(6-bromo-3-fluoro-pyridin-2-yl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (90 mg, 0.212 mmol),4-cyano-3-methyl-pyridine-2-carboxylic acid amide (41 mg, 0.255 mmol),XANTPHOS (11.05 mg, 0.019 mmol) and cesium carbonate (97 mg, 0.297 mmol)in dioxane (3 ml) was degassed with argon for 5 minutes. Pd2(dba)3 (5.83mg, 6.36 μmol) was added and the sealed vial was heated at 60° C. for 18h. The reaction mixture was diluted with water and TBME. The phases wereseparated and the aq. phase was extracted with TBME. The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and evaporated. The crude product was chromatographed oversilica gel (12 g redisep column, cyclohexane/ethyl acetate 5-40%) togive the title compound. 76 mg (71% yield).

TLC (cyclohexane/ethyl acetate 3:1) R_(f)=0.15; LCMS Rt_(H4)=1.16 min.(100% purity, ESI+505).

m) 5-Cyano-3-methyl-pyridine-2-carboxylic acid[6-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide

A solution of((R)-5-{6-[(5-cyano-3-methyl-pyridine-2-carbonyl)-amino]-3-fluoro-pyridin-2-yl}-5-difluoromethyl-4,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester (75 mg, 0.149 mmol) and TFA (115 μI, 1.48 mmol) indichloromethane was stirred at rt for 2 h. The reaction mixture wasdiluted with ethyl acetate and poured into an ice/ammonia 2M mixture.The organic layer was washed with water and brine, dried over sodiumsulfate, filtered and evaporated. 62 mg solid (quantitative yield).

TLC (dichloromethane/methanol 95/5+0.5% ammonia) R_(f)=0.21;

LCMS Rt_(H4)=0.75 min. (ESI+ 405); ¹H-NMR (400 MHz, DMSO-d₆): 10.75 (br.s, 1H, NH), 9.02 (s, 1H), 8.44 (s, 1H), 8.20 (d, 1H), 7.78 (t, 1H), 6.36(t, 1H, CHF₂), 6.06 (br. s, 2H, NH₂), 4.27 (d, 1H, AB), 4.04-3.86 (m,3H, AB), 2.61 (s, 3H).

Example 39: 5-Cyano-3-methyl-pyridine-2-carboxylic acid[6-((S)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide

Example 39 (enantiomer of Example 38) was prepared in analogy to Example38 with intermediate (S)-2-Methyl-propane-2-sulfinic acid[(S)-1-(6-bromo-3-fluoro-4-triethylsilylanyl-pyridin-2-yl)-2,2-difluoro-1-hydroxymethyl-ethyl]-amidefrom step e).

LCMS Rt_(H4)=0.75 min. (ESI+ 405); ¹H-NMR (400 MHz, DMSO-d₆): 10.75 (br.s, 1H, NH), 9.02 (s, 1H), 8.44 (s, 1H), 8.20 (d, 1H), 7.78 (t, 1H), 6.36(t, 1H, CHF₂), 6.06 (br. s, 2H, NH₂), 4.27 (d, 1H, AB), 4.04-3.86 (m,3H, AB), 2.61 (s, 3H).

Example 40: 3-Chloro-5-cyano-pyridine-2-carboxylic acid[6-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide

Example 40 was prepared in analogy to Example 38 using Amide-2 in stepm).

LCMS Rt_(H12)=0.66 min. (ESI+ 424); ¹H-NMR (400 MHz, DMSO-d₆): δ 11.22(br. s, 1H, NH), 9.11 (s, 1H), 8.81 (s, 1H), 8.16 (dd, 1H), 7.79 (dd,1H), 6.31 (t, 1H), 6.04 (br. s, 2H, NH₂), 4.29 (d, 1H, AB), 3.96 (dd,2H), 3.87 (d, 1H, AB).

Examples 41 to 48

The compounds in Table 11 were prepared by similar procedures asdescribed for Example 11 or Example 24 and using Acids 5, 6, 7, 8 and 9for Examples 42, 43, 45, 47 and 48 respectively.

TABLE 11 MS [m/z; Example Compound ¹H-NMR (M + 1)⁺] 41

  3,5-Dimethyl-pyrazine-2-carboxylic acid[6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide (δ; DMSO-d₆,400 MHz): 10.44 (br. s, 1H, NH), 8.52 (s, 1H), 8.15 (br. d, 1H), 7.74(dd, 1H), 5.90 (br. s, 2H, NH₂), 4.12 (d, 1H, AB), 3.73 (d, 1H, AB),2.80 (s, 3H), 2.57 (s, 3H), 1.50 (s, 3H), 1.48 (s, 3H). LCMS: Rt_(H13) =0.79; [M + 1]⁺ = 440.2 42

  3-Amino-5-(3-fluoro-propoxy)-pyrazine-2-carboxylic acid[6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide (δ;DMSO-d₆, 400 MHz): 9.88 (br. s, 1H, NH), 8.12 (dd, 1H), 7.72 (dd, 1H),7.57 (s, 1H), 5.90 (br s, 2H, NH₂), 4.68 (t, 1H), 4.56 (t, 1H), 4.42 (t,2H), 4.12 (d, 1H, AB), 3.73 (d, 1H, AB), 2.20-2.11 (m, 2H), 1.51 (s,3H), 1.48 (s, 3H). LCMS: Rt_(H4) = 0.91; [M + 1]⁺ = 503.0 43

  3-Amino-5-(2-methoxy-ethyl)-5H-pyrrolo[2,3-b]pyrazine- 2-carboxylicacid [6-((3R,6R)-5-amino- 3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide (δ; DMSO-d₆,400 MHz): 10.26 (br. s, 1H, NH), 8.18 (dd, 1H), 7.74 (dd, 1H), 7.63 (d,1H), 7.51 (br. s, 2H, NH₂), 6.58 (d, 1H), 5.92 (br. s, 2H, NH₂), 4.26(t, 2H), 4.15 (d, 1H, AB), 3.78 (d, 1H, AB), 3.70 (t, 2H), 3.32 (s, 3H),1.53 (s, 3H), 1.51 (s, 3H). LCMS: Rt_(H12) = 0.84; [M + 1]⁺ = 525.2 44

  3-Amino-5-trifluoromethyl-pyrazine-2-carboxylic acid[6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide (δ;DMSO-d₆, 400 MHz): 10.24 (br. s, 1H, NH), 8.37 (s, 1H), 8.12 (dd, 1H),7.78 (dd, 1H), 5.91 (br. s, 2H, NH₂), 4.15 (d, 1H, AB), 3.75 (d, 1H,AB), 1.52 (s, 3H), 1.51 (s, 3H). LCMS: Rt_(H12) = 0.86; [M + 1]⁺ = 496.445

  3-Amino-5-(2,2-difluoro-ethyl)-5H-pyrrolo[2,3-b]pyrazine- 2-carboxylicacid [6-((3R,6R)-5-amino-3,6- dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide (δ; DMSO-d₆, 400 MHz):10.23 (s broad, 1H, NH), 8.14 (dd, 1H), 7.76 (dd, 1H), 7.60 (d, 1H),7.55 (s broad, 2H, NH₂), 6.64 (d, 1H), 6.41 (tt, 1H), 5.90 (s broad, 2H,NH₂), 4.54 (td, 2H), 4.12 (d, 1H, AB), 3.75 (d, 1H, AB), 1.50 (s, 3H),1.48 (s, 3H). LCMS: Rt_(H12) = 0.87; [M + 1]⁺ = 531.1 46

  4-Chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid[6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide (δ;DMSO-d₆, 400 MHz): 10.15 (br. s, 1H, NH), 8.80 (s, 1H), 8.03 (dd, 1H),7.92 (t, 1H), 7.75 (dd, 1H), 5.88 (br. s, 2H, NH₂), 4.14 (d, 1H, AB),3.73 (d, 1H, AB), 1.52 (s, 3H), 1.48 (s, 3H). LCMS: Rt_(H12) = 0.79;[M + 1]⁺ = 485.5-487.1 47

  6-Chloro-1-(2,2-difluoro-ethyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylic acid [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide (δ; DMSO-d₆, 400 MHz):10.77 (br. s, 1H, NH), 8.37 (s, 1H), 8.17 (dd, 1H), 7.88 (d, 1H), 7.72(dd, 1H), 6.81 (d, 1H), 6.44 (tt, 1H), 5.87 (br. s, 2H, NH₂), 4.84 (td,2H), 4.14 (d, 1H, AB), 3.73 (d, 1H, AB), 1.52 (s, 3H), 1.49 (s, 3H).LCMS: Rt_(H12) = 0.86; [M + 1]⁺ = 549.1 48

  6-Chloro-1-(2-methoxy-ethyl)-1H-pyrrolo[3,2-b]pyridine- 5-carboxylicacid [6-((3R,6R)-5-amino-3,6- dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide (δ; DMSO-d₆, 400 MHz):10.72 (br. s, 1H, NH), 8.30 (s, 1H), 8.17 (dd, 1H), 7.87 (d, 1H), 7.72(dd, 1H), 6.73 (d, 1H), 5.88 (br. s, 2H, NH₂), 4.44 (t, 2H), 4.15 (d,1H, AB), 3.74 (d, 1H, AB), 3.67 (t, 2H), 3.22 (s, 3H), 1.52 (s, 3H),1.49 (s, 3H). LCMS: Rt_(H12) = 0.86; [M + 1]⁺ = 543.2

Preparation of Intermediates

The substituted acid building blocks were either commercially availableor can be prepared as described in the literature e.g. DE19725802A1,Tetrahedron: Asymmetry 1999, 10(4), 679-687, or in an analogous manner,or can be prepared as described hereafter or in an analogous manner.

Acid 1: 5-Cyano-3-methyl-pyridine-2-carboxylic acid a)5-Bromo-3-methyl-pyridine-2-carboxylic acid tert-butyl ester

To a solution of 5-bromo-3-methyl-pyridine-2-carboxylic acid (10.20 g,47.2 mmol) and di-tert-butyldicarbonate (20.61 g, 94 mmol) in 100 ml THFwere added DMAP (0.577 g). Evolution of CO₂ started immediately and themixture was stirred for 2 h at rt. TBME and sat aq NaHCO₃ were added.The layers were separated and the organic layer washed with sat aqNaHCO₃ and brine, and dried with MgSO₄.H₂O. Chromatography on silica gel(hexanes/EtOAc 1-7%) provided the title compound as a yellow liquid.

HPLC: Rt_(H3)=3.018 min; ESIMS [M+H]⁺=272, 274 (1 Br); ¹H-NMR (360 MHz,CDCl₃): δ 8.59 s, 1H), 7.77 (s, 1H), 2.52 (s, 3H), 1.65 (s, 9H).

b) 5-Bromo-3-methyl-pyridine-2-carboxylic acid tert-butyl ester

A mixture of 5-bromo-3-methyl-pyridine-2-carboxylic acid tert-butylester (6.0 g, 22.05 mmol), Zn(CN)₂ (1.813 g, 15.43 mmol), Zn powder(0.144 g, 2.205 mmol) and Pd₂(dba) ₃.CHCl₃ (0.571 g, 0.551 mmol) weresuspended in 10 ml DMF under nitrogen atmosphere. tBu₃P (0.321 ml, 1.323mmol) was added and the mixture was stirred for 5 h at 60° C. Afterbeing cooled down the mixture was diluted with TBME, filtered overcelite and washed with brine three times. The crude product was purifiedby column chromatography on silica gel (hexanes/EtOAc 5-15%) to give thetitle compound as an off white solid. TLC (hexanes/EtOAc 3:1):R_(f)=0.31; HPLC: Rt_(H3)=2.431 min; ESIMS [M+Na]⁺=241; ¹H-NMR (360 MHz,CDCl₃): δ 8.78 (s, 1H), 7.88 (s, 1H), 2.56 (s, 3H), 1.67 (s, 9H); Ft-IR:2231 cm⁻¹ (CN).

c) 5-cyano-3-methyl-pyridine-2-carboxylic acid

To a solution of 5-cyano-3-methyl-pyridine-2-carboxylic acid tert-butylester (8.50 g, 38.9 mmol) in 1,3-dimethoxybenzene (51 ml, 389 mmol) wasadded TFA (85 ml) and stirred for 6.5 h. The reaction mixture wasdiluted with toluene and evaporated. The residue was taken up in tolueneand evaporated (2×). The product was crystallized from TBME/hexanes togive the title compound as a white powder. HPLC: Rt_(H1)=2.314 min;ESIMS [M+Na]⁺=163; ¹H-NMR (360 MHz, CDCl₃): δ 8.77 (s, 1H), 8.07 (s,1H), 2.87 (s, 3H).

Acid 2: 5-Chloro-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylicacid

A suspension of 500 mg (2.91 mmol)5-chloro-3-methyl-pyridine-2-carboxylic acid (CAS Nr.: 886365-46-4) in 9ml of D₂O (99.96% D) was treated with 1 ml of a 40% solution of NaOD inD₂O. The homogeneous solution was heated in a 100 ml Teflon vessel witha Synthos 3000 Microwave apparatus. The mixture was heated at 160° C.for 5 h and cooled down. 1H-NMR and MS analyses of the product showedthat deuteration had progressed to a high degree. Only minor amounts oftetradeutero derivatives were present. The reaction mixture wasacidified to pH3 with 2N HCl and extracted with EtOAc. The org. phasewas dried with MgSO₄.H₂O and evaporated to give the title compound as awhite solid, pure enough for further transformations.

HPLC: Rt_(H1)=2.820 min; ESIMS [M+H]⁺=177 (5D); ¹H-NMR (360 MHz, D₂O): 6non deuterated impurities.

Acid-3: 3-Amino-5-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid a)3-Amino-5-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid methylester

A mixture of 2,2,2-trifluorethanol (6.9 ml, 96 mmol) and cesiumcarbonate (1.56 g, 4.8 mmol) was stirred for 20 min,3-amino-5-chloro-pyrazine-2-carboxylic acid methyl ester (600 mg, 3.2mmol; GB 1248146) was added and the mixture was stirred at rt for 42 h.To complete the reaction the mixture was heated to reflux for another 3h. Saturated aq. NH₄Cl was added and the mixture was extracted withEtOAc, the combined organic layers were washed with saturated aq. sodiumchloride, dried with Na₂SO₄ and evaporated. The residue was purified bychromatography on silica gel (cyclohexane to cyclohexane/EtOAc 3:7) toprovide the title compound as colorless solid.

HPLC: Rt_(H4)=0.83 min; ESIMS [M+H]⁺=252.2; ¹H-NMR (400 MHz, DMSO-d₆): δ7.66 (s, 1H), 7.60 (br s, 2H), 5.03 (q, 2H), 3.81 (s, 3H).

b) 3-Amino-5-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid

To a solution of3-amino-5-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid methylester (400 mg, 1.59 mmol) in 20 ml THF was added 2.5 ml (2.5 mmol) 1Nsodium hydroxide and the mixture was stirred at room temperature overnight. To the mixture were added (2.39 ml, 2.39 mmol) 1N HCl afterstirring for 5 min toluene was added and the solvents were evaporated toprovide the title compound together with sodium chloride as an off-whitesolid. The mixture was used for coupling reactions without furtherpurification.

HPLC: Rt_(H4)=0.71 min; ESIMS [M+H]⁺=238.2; ¹H NMR (400 MHz, DMSO-d₆): δ7.46 (s, 1H), 4.97 (q, 2H).

Acid-4: 3-Amino-5-cyano-pyridine-2-carboxylic acid a)5-Bromo-3-nitro-pyridine-2-carboxylic acid tert-butyl ester

To an ice cooled solution of 5-bromo-3-nitro-pyridine-2-carboxylic acid(4.84 g, 19.59 mmol, CAS 954240-89-2) in THF (59 ml) was added DMAP (239mg, 1.96 mmol) and Boc₂O (5.56 g, 25.5 mmol) and the reaction mixturewas heated to 60° C. for 3 h. After cooling to 0° C. half saturated aq.sodium bicarbonate was added and the mixture extracted with EtOAc. Thecombined organic layers were washed with water and half saturated aq.NaCl, dried with Na₂SO₄ and evaporated. The residue was purified bychromatography on silica gel (cyclohexane to cyclohexane/EtOAc 3:2) toprovide the title compound as pale beige solid.

HPLC: Rt_(H5)=1.17 min; ESIMS [M+H]⁺=304.1; ¹H-NMR (600 MHz, DMSO-d₆): δ9.11 (s, 1H), 8.92 (s, 1H), 1.53 (s, 9H).

b) 5-Cyano-3-nitro-pyridine-2-carboxylic acid tert-butyl ester

To a solution of 5-bromo-3-nitro-pyridine-2-carboxylic acid tert-butylester (888 mg, 2.93 mmol) in DMF (8.8 ml) was added zinc cyanide (206mg, 1.76 mmol) and zinc dust (2 mg, 0.03 mmol). The mixture was purgedwith nitrogen (3 times) bis(tri-tert-butylphosphine)palladium(0) (150mg, 0.293 mmol) was added and the mixture was heated to 80° C. for 4 h.After cooling to 0° C. water was added and the mixture extracted withEtOAc, the combined organic layers were washed with half saturated aq.NaCl, dried with Na₂SO₄ and evaporated. The residue was purified bychromatography on silica gel (cyclohexane to cyclohexane/EtOAc 1:4) toprovide the title compound as beige solid.

HPLC: Rt_(H5)=1.04 min; ESIMS [M+H]⁺=248.0; ¹H-NMR (600 MHz, DMSO-d₆): δ9.39 (s, 1H), 9.29 (s, 1H), 1.55 (s, 9H).

c) 3-Amino-5-cyano-pyridine-2-carboxylic acid tert-butyl ester

To a mixture of 5-cyano-3-nitro-pyridine-2-carboxylic acid tert-butylester (130 mg, 0.522 mmol) in water (3 ml) was added acetic acid (0.149ml, 2.61 mmol), the mixture was stirred at room temperature for 20 min,sodium dithionite (454 mg, 2.61 mmol) was added and stirring wascontinued for 23 h. Additional sodium dithionite (182 mg, 1.043 mmol)was added and the reaction mixture stirred for another 48 h. The mixturewas extracted with DCM, the combined organic layers were washed withwater and saturated aq. NaCl, dried with Na₂SO₄ and evaporated toprovide the title compound as yellow solid. The product was used for thenext step without further purification.

HPLC: Rt_(H4)=0.86 min; ESIMS [M+H]⁺=220.2; ¹H-NMR (400 MHz, DMSO-d₆): δ8.15 (d, 1H), 7.61 (d, 1H), 6.95 (br. s, 2H), 1.55 (s, 9H).

d) 3-Amino-5-cyano-pyridine-2-carboxylic acid

To a mixture of 3-amino-5-cyano-pyridine-2-carboxylic acid tert-butylester (60 mg, 0.274 mmol) and 1,3-dimethoxybenzene (0.358 ml, 2.74 mmol)was added dropwise within 10 min TFA (0.59 ml, 7.66 mmol) and thereaction mixture was stirred for 6 h. Toluene was added and the solventswere evaporated to provide the title compound as yellow solid. Theproduct was used for the next step without further purification.

HPLC: Rt_(H4)=0.38 min; ESIMS [M+H]⁺=164.1; ¹H-NMR (400 MHz, DMSO-d₆): δ13.05 (br. s, 1H), 8.16 (d, 1H), 7.64 (d, 1H), 7.08 (br. s, 2H).

Acid-5:3-(Di-tert-butoxycarbonyl-amino)-5-(3-fluoro-propoxy)-pyrazine-2-carboxylicacid a)3-(Di-tert-butoxycarbonyl-amino)-5-(3-fluoro-propoxy)-pyrazine-2-carboxylicacid 3-fluoro-propyl ester

About a 1:1 mixture of3-(di-tert-butoxycarbonyl-amino)-5-(3-fluoro-propoxy)-pyrazine-2-carboxylicacid methyl ester and3-(di-tert-butoxycarbonyl-amino)-5-(3-fluoro-propoxy)-pyrazine-2-carboxylicacid 3-fluoro-propyl ester was obtained following the proceduredescribed for acid-3 step a).

To an ice cooled solution of this mixture (245 mg, 0.89 mmol), DIPEA(1.31 ml, 7.48 mmol) and DMAP (13 mg, 0.11 mmol) in DCM (10 ml) wasadded a solution of Boc₂O (1.05 g, 4.81 mmol) in DCM (10 ml) and themixture was stirred and allowed to warm to r.t. overnight. Afteraddition of water the mixture was extracted with EtOAc (3×) and thecombined organic layers were washed with 0.5N HCl, saturated aq. sodiumchloride, dried with Na₂SO₄ and evaporated. The residue was purified bychromatography on silica gel (cyclohexane+5% NEt₃ to cyclohexane+0.5%NEt₃/EtOAc+0.5% NEt₃ 3:7) to provide the title compound together withthe3-(di-tert-butoxycarbonyl-amino)-5-(3-fluoro-propoxy)-pyrazine-2-carboxylicacid methyl ester as yellow viscous oil. This mixture was used for thenext step.

HPLC: Rt_(H4)=1.19 min; ESIMS [M+H]⁺=476.3; (Me-Ester: HPLC:Rt_(H4)=1.15 min; ESIMS [M+H]⁺=430.3).

b)3-(Di-tert-butoxycarbonyl-amino)-5-(3-fluoro-propoxy)-pyrazine-2-carboxylicacid

To a solution of3-(di-tert-butoxycarbonyl-amino)-5-(3-fluoro-propoxy)-pyrazine-2-carboxylicacid 3-fluoro-propyl ester and3-(di-tert-butoxycarbonyl-amino)-5-(3-fluoro-propoxy)-pyrazine-2-carboxylicacid methyl ester (395 mg, 0.92 mmol) in THF (10 ml) was added 0.5N LiOH(2.02 ml, 1.01 mmol) and the mixture was stirred for 5.5 h. To thereaction mixture was added 1N HCl (0.92 ml, 0.92 mmol) after stirringfor 5 min toluene was added and the solvents were evaporated to providethe title compound together with lithium chloride as a light yellowsolid. The mixture was used for coupling reactions without furtherpurification.

HPLC: Rt_(H4)=0.98 min; ESIMS [M-Boc+H]⁺=316.2; ¹H NMR (400 MHz,DMSO-d₆): δ 8.26 (s, 1H), 4.67 (t, 1H), 4.55 (t, 1H), 4.41 (t, 2H),2.22-2.07 (m, 2H), 1.32 (s, 18H).

Acid-6:3-Amino-5-(2-methoxy-ethyl)-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acida) 3-Amino-6-bromo-5-(2-methoxy-ethylamino)-pyrazine-2-carboxylic acidmethyl ester

To a mixture of 3-amino-5,6-dichloro-pyrazine-2-carboxylic acid methylester [CAS 1458-18-0] and 3-amino-6-bromo-5-chloro-pyrazine-2-carboxylicacid methyl ester [CAS 14340-25-1] (799 mg, 3 mmol) in DMF was added2-methoxy-ethylamine (0.31 ml, 3.6 mmol) and NEt₃ (2.09 ml, 15 mmol) andthe mixture was stirred at r.t. for 3.5 h. The reaction mixture waspoured into water (150 ml) and extracted with toluene (2×150 ml). Theorganic layers were washed with half-saturated aq. sodium chloride,combined, dried with Na₂SO₄ and evaporated. The residue was purified bychromatography on silica gel (cyclohexane/EtOAc 100:0 to 0:100%) toprovide the title compound together with3-amino-6-chloro-5-(2-methoxy-ethylamino)-pyrazine-2-carboxylic acidmethyl ester (about 1:1) as colorless solid. This mixture was used forthe next step.

HPLC: Rt_(H4)=0.77 min; ESIMS [M+H]⁺=305.1; (Cl-pyrazine: HPLC:Rt_(H4)=0.73 min; ESIMS [M+H]⁺=261.1).

b)3-Amino-5-(2-methoxy-ethylamino)-6-trimethylsilanylethynyl-pyrazine-2-carboxylicacid methyl ester

To a solution of ethynyl-trimethyl-silane (1.05 g, 10.7 mmol),bis(triphenylphosphine)palladium(II) chloride (150 mg, 0.214 mmol),Copper(I) iodide (41 mg, 0.214 mmol) and NEt₃ (2.09 ml, 14.98 mmol) inTHF (17 ml) was added under an argon atmosphere a mixture (about 1:1) of3-amino-6-bromo-5-(2-methoxy-ethylamino)-pyrazine-2-carboxylic acidmethyl ester and3-amino-6-chloro-5-(2-methoxy-ethylamino)-pyrazine-2-carboxylic acidmethyl ester (651 mg, 2.14 mmol) and the mixture was heated to 80° C.for 17 h. The reaction mixture was filtered through Hyflo and thesolvent evaporated. The residue was purified by chromatography on silicagel (cyclohexane to cyclohexane/EtOAc 60:40) to provide the titlecompound as brown solid.

HPLC: Rt_(H4)=1.12 min; ESIMS [M+H]⁺=323.3; ¹H NMR (400 MHz, DMSO-d₆): δ7.46 (br, 2 H), 6.65 (t, 1H), 3.73 (s, 3H), 3.59-3.45 (m, 4H), 3.28 (s,3H), 0.25 (s, 9H).

c) 3-Amino-5-(2-methoxy-ethyl)-5H-pyrrolo[2,3-b]pyrazine-2-carboxylicacid

To a solution of3-amino-5-(2-methoxy-ethylamino)-6-trimethylsilanylethynyl-pyrazine-2-carboxylicacid methyl ester (487 mg, 1.51 mmol) in THF (7.6 ml) was added asuspension of KOtBu (356 mg, 3.17 mmol) in THF (7.6 ml) and the reactionmixture was stirred at r.t. for 2 h. At 0° C. solid NH₄Cl (848 mg) wasadded and the mixture stirred for 30 min. After addition ofhalf-saturated NH₄Cl solution (15 ml) the mixture was extracted withEtOAc (2×15 ml), the pH of the aq. phase was adjusted the pH to 4 byaddition of 1N HCl. The aq. phase was extracted with DCM/EtOH 9:1 (2×100ml), the combined organic layers were dried with Na₂SO₄ and evaporated.The residue was filtered through a plug of silica gel (DCM/EtOH 90:10)to provide the title compound as brown powder. This material was usedfor coupling reactions without further purification.

HPLC: Rt_(H4)=0.53 min; ESIMS [M+H]⁺=237.1; ¹H NMR (600 MHz, DMSO-d₆): δ12.59 (br s, 1H), 7.55 (d, 1H), 7.26 (br s, 2H), 6.46 (d, 1H), 4.21 (t,2H), 3.66 (t, 2H), 3.22 (s, 3H).

Acid-7:3-Amino-5-(2,2-difluor-ethyl)-5H-pyrrolo[2,3-b]pyrazine-2-carboxylicacid

3-Amino-5-(2,2-difluoro-ethylamino)-6-trimethylsilanylethynyl-pyrazine-2-carboxylicacid methyl ester was prepared by similar procedures as for Acid-6(steps a and b) applying 80° C. in step a) instead of room temperature.

a) 3-Amino-5-(2,2-difluoro-ethyl)-6H-pyrrolo[2,3-b]pyrazine-2-carboxylicacid methyl ester

To a solution of3-amino-5-(2,2-difluoro-ethylamino)-6-trimethylsilanylethynyl-pyrazine-2-carboxylicacid methyl ester (624 mg, 1.9 mmol) in DMF (19 ml) was added Copper(I)iodide (181 mg, 0.95 mmol) and the mixture was heated to 120° C. for 2h. The reaction mixture was filtered through Hyflo, the residue washedwith toluene. The combined organic phases were extracted with water,dried with Na₂SO₄ and evaporated. The residue was purified bychromatography on silica gel (cyclohexane to cyclohexane/EtOAc 40:60) toprovide the title compound as yellow solid.

HPLC: Rt_(H4)=0.67 min; ESIMS [M+H]⁺=257.1; ¹H NMR (400 MHz, DMSO-d₆): δ7.64-7.51 (m, 1H), 7.27 (br s, 2H), 6.56 (m, 1H), 6.43 (t, 1H),4.62-4.46 (m, 2H), 3.86 (s, 3H).

b) 3-Amino-5-(2,2-difluor-ethyl)-5H-pyrrolo[2,3-b]pyrazine-2-carboxylicacid

To a solution of3-amino-5-(2,2-difluoro-ethyl)-6H-pyrrolo[2,3-b]pyrazine-2-carboxylicacid methyl ester (192 mg, 0.749 mmol) in THF (3.8 ml) was added asolution of 1M LiOH (0.824 ml, 0.824 mmol) and the reaction mixture wasstirred at r.t. for 20 h. At 0° C. 1M HCl (0.749 ml) was added and themixture diluted with toluene (7.5 ml). The solvents were evaporated toprovide the title compound together with LiCl as brown powder. Thismaterial was used for coupling reactions without further purification.

HPLC: Rt_(H4)=0.57 min; ESIMS [M+H]⁺=243.1; ¹H NMR (600 MHz, DMSO-d₆): δ12.71 (br s, 1H), 7.56 (d, 1H), 7.35 (br s, 2H), 6.55 (d, 1H), 6.41 (t,1H), 4.61-4.43 (m, 2H).

Acid-8:6-Chloro-1-(2,2-difluoro-ethyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylicacid a)6-Chloro-1-(2,2-difluoro-ethyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylicacid ethyl ester

To a solution of 6-chloro-1H-pyrrolo[3,2-b]pyridine-5-carboxylic acidethyl ester (210 mg, 0.935 mmol) in DMF (10 ml) was added cesiumcarbonate (457 mg, 1.402 mmol), after 15 min stirring at roomtemperature 1,1-difluoro-2-iodoethane (538 mg, 2.8 mmol) was added andstirring was continued over night. Tetrabutylammonium iodide (34.5 mg,0.093 mmol) was added and stirring was continued for another 48 h. Tothe reaction mixture was added saturated aq. NH4Cl and the mixture wasextracted with MTBE (2×). The combined organic layers were washed withhalf-saturated aq. NaCl, dried with Na₂SO₄ and evaporated. The residuewas purified by chromatography on silica gel (cyclohexane tocyclohexane/EtOAc 20:80) to provide the title compound as yellow solid.

HPLC: Rt_(H4)=0.88 min; ESIMS [M+H]⁺=289.4/291.1; ¹H NMR (400 MHz,DMSO-d₆): δ 8.34 (s, 1H), 7.83 (d, 1H), 6.74 (d, 1H), 6.40 (t, 1H), 4.78(td, 2H), 4.35 (q, 2H), 1.31 (t, 3H).

b)6-Chloro-1-(2,2-difluoro-ethyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylicacid

To a solution of6-chloro-1-(2,2-difluoro-ethyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylicacid ethyl ester (150 mg, 0.520 mmol) in THF (10 ml) was added 1N aq.sodium hydroxide (0.624 ml, 0.624 mmol) and mixture was stirred at 65°C. for 4.5 h. The solvents were evaporated, the residue was dissolved inwater, acidified with 2N aq. HCl and the mixture extracted with EtOAc.The combined organic layers were dried with Na₂SO₄ and evaporated toprovide the title compound as light orange solid.

HPLC: Rt_(H4)=0.50 min; ESIMS [M+H]⁺=261.0/263.1; ¹H NMR (400 MHz,DMSO-d₆): δ 13.36 (s, 1H), 8.31 (s, 1H), 7.81 (d, 1H), 6.72 (d, 1H),6.39 (t, 1H), 4.87-4.67 (m, 2H).

Acid-9:6-Chloro-1-(2-methoxy-ethyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylic acid

6-Chloro-1-(2-methoxy-ethyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylic acidwas prepared by similar procedures as for Acid-9 [steps a) and b)] using1-bromo-2-methoxy-ethane in step a) instead of1,1-difluoro-2-iodo-ethane without addition of tetrabutylammonium iodideand stirring only once over night.

HPLC: Rt_(H4)=0.47 min; ESIMS [M+H]⁺=255.1/257.1; ¹H NMR (400 MHz,DMSO-d₆): δ 13.26 (br. s, 1H), 8.22 (s, 1H), 7.79 (d, 1H), 6.63 (d, 1H),4.38 (t, 2H), 3.62 (t, 2H), 3.17 (s, 3H).

Amide 1: 5-Cyano-3-methyl-pyridine-2-carboxylic acid amide

To a white suspension of 5-cyano-3-methyl-pyridine-2-carboxylic acid (84mg, 0.518 mmol) in DCM (1.5 ml) was added oxalyl chloride (0.068 ml, 99mg, 0.777 mmol) and a catalytic amount of DMF. The reaction mixture wasstirred at rt for 1 h and was then added dropwise to a 25% aq. NH₄OHsoln. (0.300 ml) at 0° C. The reaction mixture was stirred for 10 min atrt, H₂O and TBME were added, the phases were separated and the aq. phasewas twice reextracted with TBME. The combined org. phases were driedover Na₂SO₄, filtered and concentrated to leave a white powder that wasused in the next step without further purification. Rt_(H4)=0.47 min;ESIMS: 162 [(M+H)⁺]; ¹H NMR (400 MHz, DMSO-d₆): δ 8.68 (d, 1H), 7.91 (d,1H), 7.80 (br s, 1H), 5.57 (br s, 1H), 2.80 (s, 3H).

Amide 2: 3-Chloro-5-cyano-pyridine-2-carboxylic acid amide was preparedfrom 3-chloro-5-cyano-pyridine-2-carboxylic acid (CAS 1200497-81-9) inanalogy to the procedure described for Amide 1.

Rt_(H4)=0.45 min;

¹H NMR (400 MHz, DMSO-d₆): δ 9.01 (d, 1H), 8.70 (d, 1H), 8.17 (br s,1H), 7.94 (br s, 1H).

Amide 3: 3-Chloro-5-difluoromethoxy-pyridine-2-carboxylic acid amide wasprepared from 3-chloro-5-difluoromethoxy-pyridine-2-carboxylic acid (CAS1262860-72-9) in analogy to above procedure. Rt_(H4)=0.62 min; ESIMS:223 [(M+H)⁺];

¹H NMR (400 MHz, DMSO-d₆): δ 8.49 (d, 1H), 8.08-7.97 (m, 2H), 7.73 (brs, 1H), 7.45 (t, 1H).

Hydroxyester 1: 3-Fluoro-2-fluoromethyl-2-hydroxy-propionic acid ethylester a) 3-Fluoro-2-fluoromethyl-2-trimethylsilanyloxy-propionitrile

To 1,3-difluoro-propan-2-one (8.5 g, 90 mmol) was added drop wise over30 min TMS-Cyanide (8.97 g, 90 mmol). The reaction mixture was stirredfor 16 h at ambient temperature. Yield=17.4 g (100%).

¹H-NMR (400 MHz, CDCl₃) δ 4.55 (d, 2H), 4.44 (d, 2H), 0.28 (s, 9H).

¹⁹F-NMR (376 MHz, CDCl₃) δ −226 (t).

b) 3-Fluoro-2-fluoromethyl-2-hydroxy-propionic acid

3-Fluoro-2-fluoromethyl-2-trimethylsilanyloxy-propionitrile (17.4 g, 90mmol) was treated with 37% HCl (300 ml) and heated to gentle reflux for3 h. The reaction mixture was cooled to ambient temperature andconcentrated in vacuo. The solid thus obtained was redissolved in 300 mlethanol and concentrated in vacuo and dried in high vacuum.

The solid thus obtained (17 g) contained significant amount ofammonium-chloride and was used without further purification.

¹H-NMR (400 MHz, DMSO-d₆) δ 7.0-7.3 (m, 4H), 5.6-6.5 (s, 1H), 4.43-4.58(m, 4H).

¹³C-NMR (150 MHz, DMSO-d₆) δ 171 (t), 85 (d), 83 (d), 75 (t).

c) 3-Fluoro-2-fluoromethyl-2-hydroxy-propionic acid ethyl ester

Crude 3-fluoro-2-fluoromethyl-2-hydroxy-propionic acid (17 g) wasdissolved in ethanol (400 ml) and H₂SO₄ (98%, 30 g) was added. Thereaction mixture was refluxed for 16 h. The reaction mixture was cooledto ambient temperature and filtered. The solution was carefully treatedwith 30 g solid Na₂CO₃ and the resulting mixture was stirred for 30 minat room temperature. 400 ml DCM were added and the mixture was filtered.The solution was concentrated (50° C., 150 mbar) and further purified bydistillation (82° C., 20 mbar) to give a colorless liquid.

Yield=9.8 g (97%).

¹H-NMR (400 MHz, DMSO-d₆) δ 4.43-4.65 (m, 4H), 4.30 (q, 2H), 3.63-3.88(s, 1H), 1.30 (t, 3H).

The invention claimed is:
 1. A process for the preparation of a compoundof the formula (I)

or a salt thereof, in which X₁ is CR₁ or N; X₃ is CR₃ or N; X₄ is CR₄ orN; X₅ is CR₅ or N; wherein at least one of X₁, X₃, X₄ and X₅ is N andnot more than 2 of X₁, X₃, X₄ and X₅ are N; R₁ is hydrogen, cyano,halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy,halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,(C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,(C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,(C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,(C₂₋₈)alkenyl, or (C₂₋₈)alkynyl; R₂ is an aryl, heteroaryl ornon-aromatic heterocyclyl group G₁, which group G₁ is optionallysubstituted by 1, 2, 3 or 4 substituents independently selected from thegroup, consisting of cyano, amino, amino-(C₁₋₈)alkyl,N—(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, N,N-di(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl,aminocarbonyl, thiocarbamoyl, halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl,hydroxy, oxo, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio,halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,(C₃₋₈)cycloalkyl-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,(C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,(C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,(C₂₋₈)alkenyl, (C₂₋₈)alkynyl, (C₂₋₈)alkenoxy, (C₂₋₈)alkynoxy and a(C₃₋₈)cycloalkyl, aryl, heteroaryl or non-aromatic heterocyclyl groupG₂, which group G₂ is optionally substituted by 1, 2, 3, or 4substituents independently selected from the group, consisting of cyano,aminocarbonyl, halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl, hydroxy,(C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio,halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,(C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl and (C₂₋₈)alkynyl; R₃ ishydrogen, cyano, halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl,(C₁₋₈)alkoxy; halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio,halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,(C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl, or (C₂₋₈)alkynyl; R₄ ishydrogen, cyano, halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl,(C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio,halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,(C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl, or (C₂₋₈)alkynyl; R₅ ishydrogen, cyano, halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl,(C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio,halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,(C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl, or (C₂₋₈)alkynyl; or R₄and R₅, taken together, are —C(H)═C(H)—C(H)═C(H)— or a (C₁₋₈)alkylenegroup, in which (C₁₋₈)alkylene group 1 or 2 —CH₂— ring members areoptionally replaced with hetero ring members independently selected fromthe group, consisting of —N(H)—, —N[(C₁₋₈)alkyl]-, —O—, —S—, —S(═O)— or—S(═O)₂—; R₆ is (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl, hydroxy-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkyl, mercapto-(C₁₋₈)alkyl,(C₁₋₈)alkylthio-(C₁₋₈)alkyl, amino-(C₁₋₈)alkyl,N-(C₁₋₄)alkyl-amino-(C₁₋₈₎alkyl, N,N-di(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl,(C₂₋₈)alkenyl, or (C₂₋₈)alkynyl; or R₅ and R₆, taken together, are a(C₁₋₄)alkylene group, in which (C₁₋₄)alkylene group 1 —CH₂— ring memberis optionally replaced with a hetero ring member independently selectedfrom the group, consisting of —N(H)—, —N[(C₁₋₄)alkyl]-, —O—, —S—,—S(═O)— or —S(═O)₂—; E₁ is —C(R₇)(R₈)— or —C(R₇)(R₈)—C(R₉)(R₁₀)—; E₂ is—C(R₁₁)(R₁₂)— or —C(R₁₁)(R₁₂)—C(R₁₃)(R₁₄)—; either each of R₇ and R₈ isindependently selected from the group, consisting of hydrogen, cyano,halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and(C₁₋₈)alkylthio-(C₁₋₈)alkyl; or R₇ and R₈, taken together, are oxo or—CH₂—CH₂—; either each of R₉ and R₁₀ is independently selected from thegroup, consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and(C₁₋₈)alkylthio-(C₁₋₈)alkyl; or R₉ and R₁₀, taken together, are oxo or—CH₂—CH₂—; either each of R₁₁ and R₁₂ is independently selected from thegroup, consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and(C₁₋₈)alkylthio-(C₁₋₈)alkyl; or R₁₁ and R₁₂, taken together, are oxo or—CR₁₅R₁₆—CR₁₇R₁₈— wherein R₁₅, R₁₆, R₁₇ and R₁₈ are independentlyselected from hydrogen and fluoro; and either each of R₁₃ and R₁₄ isindependently selected from the group, consisting of hydrogen, cyano,halogen, (C₁₋₈)alkyl, halogen-(C₁₋₄)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and(C₁₋₈)alkylthio-(C₁₋₈)alkyl; or R₁₃ and R₁₄, taken together, are oxo or—CH₂—CH₂—; which comprises: a) the reaction of a compound of the formula(II)

or a salt thereof, in which X₁, X₃, X₄, X₅, R₆, E₁ and E₂ are as definedfor the formula (I) and PG is a protecting group, with a compound of theformula (III)

or a salt thereof, in which R₂ is as defined for the formula (I) and Lis a leaving group; b) the reaction of a compound of the formula (IIa)

or a salt thereof, in which X₁, X₃, X₄, X₅, R₆, E₁ and E₂ are as definedfor the formula (I), Hal is halogen and PG is a protecting group, with acompound of the formula (IIIa)

or a salt thereof, in which R₂ is as defined for the formula (I); or c)the reaction of a compound of the formula (IV)

or a salt thereof, in which X₁, X₃, X₄, X₅, R₂, R₆, E₁ and E₂ are asdefined for the formula (I), with ammonia.
 2. The process of claim 1 forthe preparation of a compound of the formula (I), or a salt thereof,which comprises the reaction of a compound of the formula (II)

or a salt thereof, in which X₁, X₃, X₄, X₅, R₆, E₁ and E₂ are as definedfor the formula (I) and PG is a protecting group, with a compound of theformula (III)

or a salt thereof, in which R₂ is as defined for the formula (I) and Lis a leaving group.
 3. The process of claim 2 for the preparation of acompound of the formula (Id)

or a salt thereof, in which X₁ is CH or N; X₃ is CH or N; X₄ is CR₄ orN; wherein one and not more than one of X₁, X₃ and X₄ is N; R₂ is apyridyl or pyrazinyl group which is substituted by 2 or 3 substituentsand wherein one of the substituents is located at the para position andone of the substituents is located at the ortho position of the pyridylor pyrazinyl group relative to the amide linker and wherein thesubstituents are independently selected from the group, consisting ofcyano, amino, halogen, (C₁₋₄)alkyl, halogen-(C₁₋₄)alkyl, hydroxy, oxo,(C₁₋₄)alkoxy and halogen-(C₁₋₄)alkoxy; R₄ and R₅ are independentlyhydrogen or halogen; R₆ is methyl, fluoromethyl, difluoromethyl ortrifluoromethyl; and each of R₁₁ and R₁₂ is independently selected fromthe group, consisting of hydrogen, methyl, fluoromethyl, difluoromethyland trifluoromethyl.
 4. The process of claim 3 for the preparation of acompound of the formula (Ie)

or a salt thereof, in which R₂ is a pyridin-2-yl or pyrazin-2-yl groupwhich is substituted by 2 substituents and wherein one of thesubstituents is located at the para position and one of the substituentsis located at the ortho position of the pyridin-2-yl or pyrazin-2-ylgroup relative to the amide linker and wherein the substituents areindependently selected from the group, consisting of cyano, amino,fluoro, bromo, chloro, hydroxyl, oxo, methyl, fluoromethyl,difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxyand trifluromethoxy; R₅ is hydrogen or fluoro; R₆ is methyl,fluoromethyl or difluoromethyl; and each of R₁₁ and R₁₂ is independentlyselected from the group, consisting of hydrogen, methyl, fluoromethyl,difluoromethyl and trifluoromethyl.
 5. The process of claim 4, whereinR₅ is fluoro.
 6. The process of claim 5, wherein R₆ is methyl.
 7. Theprocess of claim 6, wherein one of R₁₁ and R₁₂ is methyl and the otherone of R₁₁ and R₁₂ trifluoromethyl.
 8. The process of claim 7, whereinR₂ is


9. The process of claim 8, wherein the compound of formula (II) is [(2R,5R)-5-(6-amino-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester.
 10. The process of claim 1, wherein the compoundof formula (I) is


11. The process of claim 2, wherein the compound of formula (I) is


12. The process of claim 11, wherein the process further comprises thecleavage of PG.